Balloon coating method

ABSTRACT

A balloon coating method is disclosed for forming a coating layer on an outer surface of a balloon of a balloon catheter. The method includes an application step where a vertically extending dispensing tube for supplying a coating solution containing the water-insoluble drug and a solvent is formed at its end portion with an opening portion for discharging the coating solution therethrough and when an opening portion-formed end portion side of the dispensing tube is kept in contact with the outer surface of the balloon in such a manner as to be oriented to a rotating direction of the balloon while the balloon is rotated about an axis of the balloon, the coating solution is discharged through the opening portion and applied to the outer surface of the balloon while the dispensing tube is moved relative to the balloon in an axial direction of the balloon.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/282,230 filed on Mar. 20, 2015, which is a continuation ofInternational Application No. PCT/JP2015/058546 filed on Mar. 20, 2015,which claims priority to Japanese Patent Application No. 2014-075322filed Apr. 1, 2014, the entire contents of which are incorporated hereinby reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to a balloon coating method for forming acoating layer containing a drug on a surface of a balloon.

BACKGROUND ART

In recent years, balloon catheters have been used for improving lesionaffected areas (stenosed parts) generated in body lumens. A ballooncatheter normally includes an elongated shaft portion, and a balloon,which is provided on the distal side of the shaft portion and isinflatable in the radial direction. After the balloon in a deflatedstate is brought to a target site in the body by way of a thin bodylumen, the balloon is inflated, whereby the lesion affected area can bepushed wide open.

If a lesion affected area is forcibly pushed wide open, however,excessive proliferation of smooth muscle cells may occur, possiblycausing new stenosis (restenosis) at the lesion affected area. In viewof this, recently, drug eluting balloons (DEBs) wherein an outer surfaceof a balloon is coated with a drug for restraining stenosis have beenused. The drug eluting balloon, by being inflated, is able toinstantaneously release the drug contained in the coating on the outersurface thereof to the lesion affected area and transfer the drug to theliving body tissue, thereby restraining restenosis.

In recent years, it has been becoming clear that the morphological formof the drug in the coating on the balloon surface influences thereleasing property of the drug from the balloon surface and/or thetissue transferability of the drug, at the lesion affected area. Forthis reason, it can be important to control the crystalline form oramorphous form of the drug.

A variety of methods have been proposed for coating a balloon with adrug. For example, U.S. Patent Application Publication No. 2010/055294describes a method in which a coating liquid containing a drug issupplied to a surface of a balloon while the balloon is moved in itsaxial direction while being rotated and while the coating quantity isbeing controlled, and the coating liquid is dried to form a coatinglayer containing the drug.

SUMMARY OF INVENTION

The drug in the coating on the outer surface of the balloon can assumedifferent morphological forms such as crystalline form, amorphous form,and mixed formed thereof, depending on various conditions such as thelength of time of volatilization of the solvent. Neither of thecrystalline form and the amorphous form is more desirable than theother, and it is desirable that the morphological form of the drug canbe selected according to the purpose.

A balloon coating method is disclosed by which the morphological formand the like of a drug in a coating formed on a balloon can be suitablyset.

A balloon coating method is disclosed for forming a coating layercontaining a water-insoluble drug on an outer surface of a balloon of aballoon catheter, the balloon coating method including an applicationstep in which, where a flexible dispensing tube for supplying a coatingsolution containing the water-insoluble drug and a solvent is formed atits end portion with an opening portion for discharging the coatingsolution therethrough and when the opening portion-formed end portionside of the dispensing tube is kept in contact with the outer surface ofthe balloon in such a manner as to be oriented in a direction oppositeto a rotating direction of the balloon while the balloon is rotatedabout an axis of the balloon, the coating solution is discharged throughthe opening portion and applied to the outer surface of the balloonwhile the dispensing tube is moved relative to the balloon in an axialdirection of the balloon.

In the balloon coating method configured as above, the coating solutionis discharged while the dispensing tube is kept in contact with theouter surface of the balloon in such a manner that the opening portionof the dispensing tube is oriented in the direction opposite to therotating direction of the balloon. By giving suitable contact betweenthe dispensing tube and the balloon, therefore, the morphological form,size and the like of the drug contained in the coating layer can be setmore freely. Particularly, for example, by discharging the coatingsolution while the opening portion of the dispensing tube is in contactwith the outer surface of the balloon so as to be oriented in thedirection opposite to the rotating direction of the balloon, thewater-insoluble drug in the coating layer formed on the outer surface ofthe balloon can be formed in a morphological form including a pluralityof elongate bodies having each independent long axes of the crystal.

In the application step, the coating solution may be discharged in astate where a continuous length of a side surface on the openingportion-formed end portion side of the dispensing tube is in contactwith the outer surface of the balloon. In this case, suitable contactcan be given between the dispensing tube and the balloon, such that thecrystals of the water-insoluble drug assume a morphological formincluding a plurality of elongate bodies having each independent longaxis.

In the application step, the coating solution may be discharged, withthe flexible dispensing tube being pressed against the outer surface ofthe balloon while being bent. In this case, it is ensured that even ifthe balloon becomes eccentric, the dispensing tube moves following up tothe balloon; therefore, the balloon can be inhibited from being damaged,and the contact of the dispensing tube with the balloon can bemaintained favorably. Consequently, the thickness and morphological formof the coating layer formed can be set with high accuracy.

In the application step, the coating solution may be discharged throughthe opening portion while the dispensing tube is kept in contact withthat portion of the balloon which is rotating toward an upper side inthe vertical direction. In this case, it can be relatively easy todispose the dispensing tube in such a manner that the opening portion isoriented in the direction opposite to the rotating direction of theballoon.

The water-insoluble drug may be rapamycin, paclitaxel, docetaxel, oreverolimus. In this case, restenosis of a stenosed part in a bloodvessel can be favorably inhibited by the aforementioned water-insolubledrug formed the crystals of which assume a morphological form includinga plurality of elongate bodies having each independent long axes.

In addition, another balloon coating method according to the presentdisclosure is a balloon coating method for forming a coating layercontaining a water-insoluble drug on an outer surface of a balloon of aballoon catheter, the balloon coating method including an applicationstep in which, where a pipe-shaped dispensing tube formed from apolyolefin for supplying a coating solution containing thewater-insoluble drug and a solvent is formed at its end portion with anopening portion for discharging the coating solution therethrough andwhen the opening portion-formed end portion side of the dispensing tubeis placed in contact with the outer surface of the balloon while theballoon is rotated about an axis of the balloon, the coating solution isdischarged through the opening portion and applied to the outer surfaceof the balloon while the dispensing tube is moved relative to theballoon in an axial direction of the balloon. In the balloon coatingmethod configured as above, the dispensing tube formed from thepolyolefin is placed in contact with the balloon, and, therefore, theaffinity of the dispensing tube for the solvent is high and the contactangle is small, as compared to the case where a fluororesin-made tube isused. For this reason, the coating solution is less liable to berepelled at the opening portion of the dispensing tube and at the partof contact with the balloon, so that unevenness of coating with thecoating solution is less liable to be generated on the outer surface ofthe balloon. Consequently, the degree of uniformity of the coating layercan be regulated with high accuracy, and the morphological form, sizeand the like of the drug contained in the coating layer can be set morefreely.

The dispensing tube may be formed from polyethylene or polypropylene. Inthis case, the affinity of the dispensing tube for organic solvents canbe securely enhanced and the contact angles can be securely reduced, ascompared to the case of a fluororesin-made tube.

In the application step, the coating solution may be discharged in astate where a continuous length of a side surface on the openingportion-formed end portion side of the dispensing tube is in contactwith the outer surface of the balloon. In this case, a suitable contactcan be given between the dispensing tube and the balloon, such that thecrystals of the water-insoluble drug assume a morphological formincluding a plurality of elongate bodies having each independent longaxis.

In addition, a coating layer control method according to the presentdisclosure is a coating layer control method for controlling the degreeof uniformity of a coating layer that contains a water-insoluble drugand is formed on an outer surface of a balloon of a balloon catheter,the coating layer control method including an application step in which,where a pipe-shaped dispensing tube formed from a polyolefin forsupplying a coating solution containing the water-insoluble drug and asolvent is formed at its end portion with an opening portion fordischarging the coating solution therethrough and when the openingportion-formed end portion side of the dispensing tube is placed incontact with the outer surface of the balloon while the balloon isrotated about an axis of the balloon, the coating solution is dischargedthrough the opening portion and applied to the outer surface of theballoon while the dispensing tube is moved relative to the balloon in anaxial direction of the balloon. In the coating layer control methodconfigured as above, the dispensing tube formed from the polyolefin isplaced in contact with the balloon, and, therefore, the affinity of thedispensing tube for the solvent is high and the contact angle is small,as compared to the case where a fluororesin-made tube is used. For thisreason, the coating solution is less liable to be repelled at theopening portion of the dispensing tube and at the part of contact withthe balloon, so that unevenness of coating with the coating solution isless liable to be generated on the outer surface of the balloon.Consequently, the degree of uniformity of the coating layer can becontrolled with high accuracy, and the morphological form, size and thelike of the drug contained in the coating layer can be set more freely.

In the application step, the dispensing tube formed from the resin maybe formed from a polyolefin or a fluororesin, and the degree ofuniformity of the coating layer may be controlled by use of thedispensing tube. In this case, while enhancing the degree of uniformityof the coating layer by use of the dispensing tube formed from thepolyolefin, unevenness of coating can be imparted to the coating layerby use of another dispensing tube formed from a fluororesin.Consequently, the level of the degree of uniformity of the coating layercan be controlled arbitrarily.

In the application step, the degree of uniformity of the coating layermay be controlled by regulating at least one of the moving speed of thedispensing tube relative to the balloon in the axial direction, thedischarge rate of the coating solution from the dispensing tube, and therotating speed of the balloon. In this case, the level of the degree ofuniformity of the coating layer can be controlled arbitrarily.

In addition, a balloon coating apparatus according to the presentdisclosure is a balloon coating apparatus for forming a coating layercontaining a water-insoluble drug on an outer surface of a ballooncatheter. The balloon coating apparatus includes a rotation mechanismportion for rotating the balloon about an axis of the balloon, apipe-shaped dispensing tube formed from a polyolefin for supplying acoating solution containing the water-insoluble drug and a solvent, anda movement mechanism portion for moving the dispensing tube relative tothe balloon in an axial direction of the balloon. In the balloon coatingapparatus configured as above, the dispensing tube is formed from apolyolefin, and, therefore, its affinity for the solvent is high and thecontact angle is small, as compared with a fluororesin-made tube. Forthis reason, the coating solution is less liable to be strongly repelledat the opening portion of the dispensing tube or at the part of contactwith the balloon, so that unevenness of coating with the coatingsolution is less liable to be generated on the outer surface of theballoon. Consequently, the degree of uniformity of the coating layer canbe controlled with high accuracy, and the morphological form, size andthe like of the drug contained in the coating layer can be set morefreely.

In addition, a further balloon coating method according to the presentdisclosure is a balloon coating method for forming a coating layercontaining a water-insoluble drug on an outer surface of a balloon of aballoon catheter in such a manner that the coating layer has regularunevenness. The balloon coating method includes an application step inwhich, where a pipe-shaped dispensing tube formed from a fluororesin forsupplying a coating solution containing the water-insoluble drug and asolvent is formed at its end portion with an opening portion fordischarging the coating solution therethrough and when the openingportion-formed end portion side of the dispensing tube is kept incontact with the outer surface of the balloon, the coating solution isdischarged through the opening portion and applied to the outer surfaceof the balloon while the dispensing tube is moved relative to theballoon in an axial direction of the balloon and while the balloon isexposed through gaps between portions of the coating solution. In theballoon coating method configured as above, the dispensing tube formedfrom the fluororesin is placed in contact with the balloon, and,therefore, the affinity of the dispensing tube for the solvent is lowand the contact angle is large. For this reason, the coating solution isstrongly repelled at the opening portion of the dispensing tube and atthe part of contact with the balloon. Accordingly, it can be relativelyeasy to apply the coating solution to the balloon while exposing theballoon through the gaps between the applied portions of the coatingsolution. Consequently, the morphological form and size of the drugcontained in the coating layer can be set more freely.

In the application step, the coating solution may be discharged in astate where a continuous length of a side surface on the openingportion-formed end portion side of the dispensing tube is kept incontact with the outer surface of the balloon. In this case, suitablecontact can be given between the dispensing tube and the balloon suchthat the crystals of the water-insoluble drug assume a morphologicalform that includes a plurality of elongate bodies having eachindependent long axis.

In the application step, the coating solution may be applied to theouter surface of the balloon in such a manner as to form a spiral linearbody. In this case, by applying the coating solution while the balloonis rotated relative to the dispensing tube, a coating layer having gapsthrough which the balloon is exposed can be formed relatively easily.

In addition, a positioning method for balloon coating according to thepresent disclosure is a positioning method for balloon coating forforming a coating layer containing a water-insoluble drug on an outersurface of a balloon of a balloon catheter. The positioning method forballoon coating includes a positioning step in which the dispensing tubeis moved, from a state of non-contact with the balloon, in a directionintersecting an extending direction of the dispensing tube, and anopening portion-formed end portion side of the dispensing tube formed atits end portion with an opening portion for discharging the coatingsolution is thereby placed in contact with the outer surface of theballoon. In the positioning method for balloon coating configured asabove, the opening portion-formed end portion side of the dispensingtube is put in contact with the outer surface of the balloon by movingthe dispensing tube in a direction intersecting the extending directionof the dispensing tube. Therefore, the burden on the balloon is light,as compared to the case where the dispensing tube is brought intocontact with the balloon in a colliding manner by moving the dispensingtube in the extending direction. For this reason, the dispensing tubeand the balloon contact with each other in a suitable state, and themorphological form, size and the like of the drug contained in thecoating layer can be set more freely. In addition, since the burden onthe balloon is reduced, it is unnecessary to provide an operating stepfor checking whether or not the balloon has been deformed or damaged.Consequently, workability can be enhanced.

The positioning method for balloon coating may further include anapplication step in which the coating solution is discharged through theopening portion and applied to the outer surface of the balloon whilethe dispensing tube is moved relative to the balloon in an axialdirection of the balloon. In this case, the coating solution can beapplied to the balloon, which is inhibited from being deformed ordamaged in the positioning step. Therefore, the quantity and thicknessof the coating solution applied to the balloon can be set with relativehigh accuracy. Consequently, the morphological form and size of the drugcontained in the coating layer can be set more freely.

In the positioning step, the dispensing tube may be moved in anextending direction of the dispensing tube without making contact withthe balloon, after which the dispensing tube may be moved in a directionintersecting the extending direction of the dispensing tube, and theopening portion for discharging the coating solution-formed end portionside of the dispensing tube may be thereby placed in contact with theouter surface of the balloon. In this case, the dispensing tube does notcontact the balloon when moved in the extending direction of thedispensing tube, and, therefore, the burden on the balloon can bereduced. For this reason, it is unnecessary to provide an operating stepfor checking whether or not the balloon has been deformed or damaged.Consequently, workability can be enhanced.

The coating solution may be discharged in a state where a continuouslength of a side surface on the opening portion-formed end portion sideof the dispensing tube is kept in contact with the outer surface of theballoon. In this case, suitable contact can be given between thedispensing tube and the balloon such that the crystals of thewater-insoluble drug assume a morphological form that includes aplurality of elongate bodies having each independent long axis.

In the case where a plane which is perpendicular to the extendingdirection of the dispensing tube in a state of non-contact with theballoon and which passes through the axis of the balloon is defined as areference plane, the dispensing tube may, in the contact step, bepositioned relative to the balloon in such a manner that a virtualposition at which the opening portion would be located if the dispensingtube is assumed to be non-flexible is located at a position deviatedfrom the reference plane toward the balloon rotating direction side byan angle within the range of 0 degrees to 40 degrees, with the axis ofthe balloon as the vertex of the angle, in a region extending from thereference plane in a direction opposite to a discharge direction of thedispensing tube. In this case, the dispensing tube can be inhibited fromslipping off from the contact position due to a frictional force betweenthe dispensing tube and the balloon. Therefore, favorable contact can bemaintained, and a desired coating layer can be formed.

In the contact step, the dispensing tube, which is flexible, may bepressed against the outer surface of the balloon while being bent. Inthis case, it is ensured that even if the balloon becomes eccentric, thedispensing tube moves following up to the balloon, so that the ballooncan be inhibited from being damaged, and favorable contact of thedispensing tube with the balloon can be maintained. Consequently, themorphological form and size of the drug contained in the coating layercan be freely set.

In addition, a positioning method for balloon coating according to thepresent disclosure is a positioning method for balloon coating forforming a coating layer containing a water-insoluble drug on an outersurface of a balloon of a balloon catheter, wherein a flexibledispensing tube is formed with an opening portion for discharging acoating solution containing the water-insoluble drug and a solvent, anda plane which is perpendicular to an extending direction of thedispensing tube in a state of non-contact with the balloon and whichpasses through an axis of the balloon is defined as a reference plane;and the positioning method includes a positioning step in which thedispensing tube is positioned relative to the balloon in such a mannerthat a virtual position at which the opening portion would be located ifthe dispensing tube is assumed to be non-flexible is located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle within the range of 0 degrees to 40 degrees,with the axis of the balloon as the vertex of the angle, in a regionextending from the reference plane in a direction opposite to adischarge direction of the dispensing tube. In the positioning methodfor balloon coating configured as above, the dispensing tube ispositioned relative to the balloon in such a manner as to be locatedwithin a range of 0 degrees to 40 degrees from the reference planetoward the rotating direction side of the balloon, with the axis of theballoon as the vertex of the angle. Therefore, the dispensing tube canbe inhibited from slipping off from the contact position due to africtional force between the dispensing tube and the balloon, andfavorable contact is maintained. Consequently, the morphological formand size of the water-insoluble drug contained in the coating layer canbe freely set.

The positioning method for balloon coating may further include anapplication step in which the coating solution is discharged through theopening portion and applied to the outer surface of the balloon whilethe dispensing tube is moved relative to the balloon in an axialdirection of the balloon. In this case, the coating solution can beapplied to the balloon by the dispensing tube, which is maintained infavorable contact with the balloon in the positioning step. Therefore,the quantity and thickness of the coating solution applied to theballoon can be set with relative high accuracy. Consequently, themorphological form and size of the drug contained in the coating layercan be set more freely.

In the positioning step, the dispensing tube may be moved in theextending direction of the dispensing tube without making contact withthe balloon, after which the dispensing tube may be moved in a directionintersecting the extending direction of the dispensing tube, and anopening portion for discharging the coating solution-formed end portionside of the dispensing tube formed with the opening portion at its endportion may be thereby placed in contact with the outer surface of theballoon. In this case, the dispensing tube does not contact the balloonwhen moved in the extending direction of the dispensing tube, so thatthe burden on the balloon is reduced. Therefore, it is unnecessary toprovide an operating step for checking whether or not the balloon hasbeen deformed or damaged. Consequently, workability can be enhanced.

The coating solution may be discharged in a state where a continuouslength of a side surface on the opening portion-formed end portion sideof the dispensing tube is kept in contact with the outer surface of theballoon. In this case, suitable contact can be given between thedispensing tube and the balloon such that the crystals of thewater-insoluble drug assume a morphological form that includes aplurality of elongate bodies having each independent long axis.

In the contact step, the flexible dispensing tube may be pressed againstthe outer surface of the balloon while being bent. In this case, it canbe relatively ensured that even if the balloon becomes eccentric, thedispensing tube moves following up to the balloon, so that the ballooncan be inhibited from being damaged, and favorable contact of thedispensing tube with the balloon can be maintained. Consequently, themorphological form and size of the drug contained in the coating layercan be set more freely.

A balloon coating method is disclosed for forming a coating layercontaining a water-insoluble drug on an outer surface of a balloon of aballoon catheter, the balloon coating method comprising: an applicationstep in which, where a vertically extending dispensing tube forsupplying a coating solution containing the water-insoluble drug and asolvent is formed at its end portion with an opening portion fordischarging the coating solution therethrough and when an openingportion-formed end portion side of the vertically extending dispensingtube is kept in contact with the outer surface of the balloon in such amanner as to be oriented to a rotating direction of the balloon whilethe balloon is rotated about an axis of the balloon, the coatingsolution is discharged through the opening portion and applied to theouter surface of the balloon while the vertically extending dispensingtube is moved relative to the balloon in an axial direction of theballoon.

A method is disclosed for forming a coating layer containing awater-insoluble drug on an outer surface of a balloon of a ballooncatheter, the method comprising: supplying a coating solution containingthe water-insoluble drug and a solvent through an distal portion of avertically extending dispensing tube with an opening portion fordischarging the coating solution through the distal portion of thevertically extending dispensing tube; keeping in contact an openingportion-formed distal portion side of the vertically extendingdispensing tube with the outer surface of the balloon in such a manneras to be oriented to a rotating direction of the balloon; rotating theballoon about an axis of the balloon; and discharging the coatingsolution through the opening portion and applied to the outer surface ofthe balloon while the vertically extending dispensing tube is movedrelative to the balloon in an axial direction of the balloon.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic view showing an apparatus for carrying out aballoon coating method according to an embodiment.

FIG. 2 is a sectional view showing a balloon catheter.

FIG. 3 is a sectional view showing a state wherein a discharge end of adispensing tube has been positioned at a reference point of a balloon,in a positioning step.

FIG. 4 is a sectional view showing a state wherein the discharge end ofthe dispensing tube has been moved in a Y-axis direction, in thepositioning step.

FIG. 5 is a sectional view showing a state wherein the discharge end ofthe dispensing tube has been moved in a Z-axis direction, in thepositioning step.

FIGS. 6A and 6B show sectional views illustrating modifications of acontact position where the dispensing tube contacts the balloon, whereinFIG. 6A shows a case where a discharge direction of the dispensing tubeis the same as the rotating direction of the balloon, while FIG. 6Bshows a case where the discharge direction of the dispensing tube isperpendicular to an outer circumferential surface of the balloon.

FIG. 7 is a diagram showing a scanning electron microscope (hereinaftersometimes referred to as SEM) image (2,000 times) of crystals observedat a substrate surface of a coating layer produced in Example 1.

FIG. 8 is a diagram showing an SEM image (1,000 times) of the crystalsobserved at the substrate surface of the coating layer produced inExample 1.

FIG. 9 is a diagram showing an SEM image (400 times) of the crystalsobserved at the substrate surface of the coating layer produced inExample 1.

FIG. 10 is a view showing an SEM image (4,000 times) of the crystalsobserved at a cross-section orthogonal to the substrate surface of thecoating layer produced in Example 1.

FIG. 11 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer produced in Example2.

FIG. 12 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer produced in Example3.

FIG. 13 is a view showing an SEM image (4,000 times) of the crystalsobserved at a cross-section orthogonal to the substrate surface of thecoating layer produced in Example 3.

FIG. 14 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer produced in Example4.

FIG. 15 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer produced in Example5.

FIG. 16 is a view showing an SEM image (1,000 times) of crystalsobserved at a substrate surface of a coating layer produced in Example6.

FIG. 17 is a view showing an SEM image (2,000 times) of the crystalsobserved at the substrate surface of the coating layer produced inExample 6.

FIG. 18 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer produced inComparative Example 1.

FIG. 19 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 7.

FIG. 20 is a view showing a laser microscope image (1,000 times) ofcrystals observed at a substrate surface of a coating layer at a centralportion P1 of the balloon shown in FIG. 19.

FIG. 21 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 8.

FIG. 22 is a view showing a laser microscope image (1,000 times) ofcrystals observed at a substrate surface of a coating layer at a centralportion P2 of the balloon shown in FIG. 21.

FIG. 23 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 9.

FIG. 24 is a view showing a laser microscope image (1,000 times) ofcrystals observed at a substrate surface of a coating layer at a centralportion P3 of the balloon shown in FIG. 23.

FIG. 25 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Comparative Example 2.

FIG. 26 is a view showing a laser microscope image (1,000 times) ofcrystals observed at a substrate surface of a coating layer at a centralportion P4 of the balloon shown in FIG. 25.

FIG. 27 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Comparative Example 3.

FIG. 28 is a view showing a laser microscope image (2,000 times) ofcrystals observed at a substrate surface of a coating layer at a centralportion P5 of the balloon shown in FIG. 27.

FIG. 29 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Comparative Example 4.

FIG. 30 is a view showing a laser microscope image (1,000 times) ofcrystals observed at a substrate surface of a coating layer at a centralportion P6 of the balloon shown in FIG. 29.

FIG. 31 is a view showing, in terms of coordinates, positions of contactof a dispensing tube with a balloon.

FIGS. 32A-32C show pictures obtained by photographing a surface of aballoon produced in Example 10, wherein FIG. 32A shows a proximalportion, FIG. 32B shows a central portion, and FIG. 32C shows a distalportion.

FIGS. 33A-33C show pictures obtained by photographing a surface of aballoon produced in Example 11, wherein FIG. 33A shows a proximalportion, FIG. 33B shows a central portion, and FIG. 33C shows a distalportion.

FIGS. 34A-34C show pictures obtained by photographing a surface of aballoon produced in Example 12, wherein FIG. 34A shows a proximalportion, FIG. 34B shows a central portion, and FIG. 34C shows a distalportion.

FIGS. 35A-35C show pictures obtained by photographing a surface of aballoon produced in Example 13, wherein FIG. 35A shows a proximalportion, FIG. 35B shows a central portion, and FIG. 35C shows a distalportion.

FIGS. 36A-36C show pictures obtained by photographing a surface of aballoon produced in Example 14, wherein FIG. 36A shows a proximalportion, FIG. 36B shows a central portion, and FIG. 36C shows a distalportion.

FIGS. 37A-37C show pictures obtained by photographing a surface of aballoon produced in Example 15, wherein FIG. 37A shows a proximalportion, FIG. 37B shows a central portion, and FIG. 37C shows a distalportion.

FIGS. 38A-38C show pictures obtained by photographing a surface of aballoon produced in Comparative Example 5, wherein FIG. 38A shows aproximal portion, FIG. 38B shows a central portion, and FIG. 38C shows adistal portion.

FIG. 39 is a sectional view showing the length of contact of adispensing tube with a balloon.

FIG. 40 is a view showing, in terms of coordinates, the positions ofcontact of a dispensing tube with a balloon, in cases of differentdispensing tube diameters.

FIG. 41 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 22.

FIG. 42 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer at a central portionof the balloon shown in FIG. 41.

FIG. 43 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 23.

FIG. 44 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer at a central portionof the balloon shown in FIG. 43.

FIG. 45 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 24.

FIG. 46 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer at a central portionof the balloon shown in FIG. 45.

FIG. 47 is a view showing a picture obtained by photographing a surfaceof a balloon produced in Example 25.

FIG. 48 is a view showing an SEM image (2,000 times) of crystalsobserved at a substrate surface of a coating layer at a central portionof the balloon shown in FIG. 47.

DETAILED DESCRIPTION

Referring to the drawings, embodiments of the present disclosure willnow be described below. Note that the dimensional ratios in the drawingsmay be exaggerated and different from the actual ratios, for convenienceof explanation.

A balloon coating method according to an embodiment of the presentdisclosure is for forming a coating layer containing a water-insolubledrug on a surface of a balloon, and is carried out by a balloon coatingapparatus 50 illustrated in FIG. 1. Note that, in the presentspecification, the side on which a balloon catheter 10 is inserted intoa body lumen will be referred to as “distal” or “distal side,” whereasthe operator's hand side on which the balloon catheter 10 is operatedwill be referred to as “proximal” or “proximal side.”

First, the structure of the balloon catheter 10 will be described. Asillustrated in FIG. 2, the balloon catheter 10 can include an elongatedcatheter main body portion 20, a balloon 30 provided at a distal portionof the catheter main body portion 20, and a hub 40 firmly attached to aproximal of the catheter main body portion 20.

The catheter main body portion 20 can include an outer tube 21 which isa pipe-shaped body opening at a distal and a proximal thereof, and aninner tube 22 disposed inside the outer tube 21. Between the outer tube21 and the inner tube 22 is formed an expansion lumen 23 through whichan expansion fluid for expanding (inflating) the balloon 30 flows. Inaddition, inside the inner tube 22 is formed a guide wire lumen 24 intoand through which a guide wire is inserted and passed.

The balloon 30 is adhered to the inner tube 22 on the distal side, andis adhered to the outer tube 21 on the proximal side, with the inside ofthe balloon 30 communicating with the expansion lumen 23. At a centralportion in an axial direction X of the balloon 30, is formed acylindrical straight portion 31 (expansion portion) having a constantouter diameter when expanded. On both sides in the axial direction X ofthe straight portion 31, are formed tapered portions 33 where theoutside diameter varies gradually. A coating layer 32 containing a drugis formed over the whole area of the outer surface of the straightportion 31. Note that the range over which the balloon 30 is formed withthe coating layer 32 is not limited only to the straight portion 31.Thus, the range may include at least part of the tapered portions 33 inaddition to the straight portion 31, or may be only part of the straightportion 31.

The hub 40 can include a first opening portion 41 which communicateswith the expansion lumen 23 of the outer tube 21 and which functions asa port through which the expansion fluid is let flow in and out, and asecond opening portion 42 into and through which the guide wire lumen 24is inserted and passed. At the second opening portion 42, there isprovided a blood stop valve 43 for inhibiting blood from flowing out.

The balloon 30 preferably has a certain degree of flexibility and acertain degree of hardness such that the drug can be released from thecoating layer 32 provided thereon when the balloon 30 is expanded uponarrival at a blood vessel or tissue. Specifically, for example, theballoon 30 is formed from metal or resin. It is preferable that at leastthe surface of the balloon 30 on which to provide the coating layer 32is formed of resin. Examples of the material which can be used forforming at least the surface of the balloon 30 include thermoplasticresins such as polyolefins (for example, polyethylene, polypropylene,polybutene, ethylene-propylene copolymers, ethylene-vinyl acetatecopolymers, ionomers, or mixtures of two or more of them), flexiblepolyvinyl chloride resin, polyamides, polyamide elastomers, polyester,polyester elastomers, polyurethane, and fluororesins, silicone rubbers,or latex rubbers. Among these, preferred, for example, are thepolyamides. Specifically, at least part of the surface of the expansionportion of the medical device to be coated with the drug is made of apolyamide. The polyamide is not particularly limited so long as it is apolymer, which has an amide linkage. Examples of the polyamide includehomopolymers such as polytetramethylene adipamide (nylon 46),polycaprolactam (nylon 6), polyhexamethylene adipamide (nylon 66),polyhexamethylene sebacamide (nylon 610), polyhexamethylene dodecamide(nylon 612), polyundecanolactam (nylon 11), and polydodecanolactam(nylon 12), copolymers such as caprolactam/lauryllactam copolymer (nylon6/12), caprolactam/aminoundecanoic acid copolymer (nylon 6/11),caprolactam/ω-aminononanoic acid copolymer (nylon 6/9), andcaprolactam/hexamethylenediammonium adipate copolymer (nylon 6/66), andaromatic polyamides such as copolymers of adipic acid withmetaxylenediamine, or copolymers of hexamethylenediamine withm,p-phthalic acid. Further, polyamide elastomers wherein nylon 6, nylon66, nylon 11, or nylon 12 constitutes hard segments and a polyalkyleneglycol, a polyether, an aliphatic polyester or the like constitutes softsegments can also be used as a base material of the medical deviceaccording to the present disclosure. The previously mentioned polyamidesmay be used either singly or in combination of two or more of them.

The balloon 30 is formed, over a surface of the base material thereof,with the coating layer 32 either directly or through a pretreatmentlayer such as a primer layer therebetween by a coating method which willbe described later.

The balloon coating apparatus 50 will now be described. As depicted inFIG. 1, the balloon coating apparatus 50 can include a rotationmechanism portion 60 which holds the balloon catheter 10 and rotates theballoon catheter 10 about an axis X of the balloon 30, a support base 70which supports the balloon catheter 10, an application mechanism portion90 provided with a dispensing tube 94 for applying a coating solution toan outer surface of the balloon 30, a movement mechanism portion 80 formoving the dispensing tube 94 relative to the balloon 30, and a controlunit 100 for controlling the balloon coating apparatus 50.

The rotation mechanism portion 60 holds the hub 40 of the ballooncatheter 10, and rotates the balloon catheter 10 by a drive source suchas a motor incorporated therein. The balloon catheter 10 is held with acore member 61 inserted in the guide wire lumen 24, and the coatingsolution is prevented by the core member 61 from flowing into the guidewire lumen 24. In addition, the balloon catheter 10 is configured insuch a manner that when the balloon 30 is expanded, the expansion fluidcan be sealed with a cap 63 put on the first opening portion 41 of thehub 40 such as to cover the expansion lumen 23.

The support base 70 can include a pipe-shaped proximal-side supportportion 71, which accommodates and rotatably supports the catheter mainbody portion 20 therein, and a distal-side support portion 72, whichsupports the core member 61 in a rotatable manner. Note that, ifpossible, the distal-side support portion 72 may support a distalportion of the catheter main body portion 20, instead of the core member61, in a rotatable manner.

The movement mechanism portion 80 can include a movable base 81 capableof moving rectilinearly in a direction parallel to the axis X of theballoon 30, and a tube positioning portion 82 on which the movable base81 is also placed and which is for moving the dispensing tube 94 in aY-axis direction and a Z-axis direction (see FIG. 5) both orthogonal tothe axis X. The movable base 81 can be moved rectilinearly by a drivesource such as a motor incorporated therein. The application mechanismportion 90 is mounted on the movable base 81, and the movable base 81moves the application mechanism portion 90 rectilinearly in bothdirections along the axis X of the balloon catheter 10. The tubepositioning portion 82 can include a tube fixing portion 83 to which thedispensing tube 94 is fixed, and a driving portion 84 for moving thetube fixing portion 83 in the Y-axis direction and the Z-axis direction.The driving portion 84 is provided for example with a biaxial sliderstructure capable of movement by a drive source such as motors orcylinders incorporated therein so that the driving portion 84 can movethe tube fixing portion 83 in both the Y-axis direction and the Z-axisdirection. Note that the Y-axis direction and the Z-axis direction inwhich the dispensing tube 94 is moved on a plane orthogonal to the axisX of the balloon catheter 10 may not necessarily be defined as thevertical direction and a horizontal direction.

The application mechanism portion 90 can include a container 92 forcontaining the coating solution, a liquid feed pump 93 for feeding thecoating solution at an arbitrary liquid feed rate, and the dispensingtube 94 for applying the coating solution to the balloon 30.

The liquid feed pump 93 is, for example, a syringe pump. While beingcontrolled by the control unit 100, the liquid feed pump 93 can suck inthe coating solution from the container 92 through a suction tube 91 andcan feed the coating solution into the dispensing tube 94 through asupply tube 96 at an arbitrary liquid feed rate. The liquid feed pump 93is disposed on the movable base 81, and can be moved rectilinearly bymovement of the movable base 81. Note that the liquid feed pump 93 isnot limited to the syringe pump so long as it can feed the coatingsolution; for example, the liquid feed pump 93 may be a tube pump.

The dispensing tube 94 is a member, which communicates with the supplytube 96, and through which the coating solution supplied from the liquidfeed pump 93 via the supply tube 96 is discharged onto the outer surfaceof the balloon 30. The dispensing tube 94 is a flexible circularpipe-shaped member. The dispensing tube 94 has an upper end fixed to thetube fixing portion 83, extends vertically downward from the tube fixingportion 83, and is formed with an opening portion 95 at a discharge end97, which is a lower end of the dispensing tube 94. By movements of themovable base 81, the dispensing tube 94 can be moved rectilinearly inboth directions along the axial direction X of the balloon catheter 10,together with the liquid feed pump 93 disposed on the movable base 81.In addition, as illustrated in FIGS. 1 and 5, the dispensing tube 94 ismovable in two different directions (in the present embodiment, in theY-axis direction which is the vertical direction and in the Z-axisdirection which is a horizontal direction) on a plane orthogonal to theaxial direction X, and is disposed in such a manner that a portion of aside surface on the end portion side of the dispensing tube 94 (aportion of a continuous length along the extending direction of thedispensing tube 94) makes contact with the balloon outer surface. Thedispensing tube 94 is capable of supplying the coating solutiontherethrough onto the outer surface of the balloon 30 in the state ofbeing pressed against the balloon 30 and bent. Alternatively, aconfiguration may be adopted wherein the end portion side of the distalof the dispensing tube 94 is preliminarily shaped and bent in such amanner as to form a certain angle in relation to the long axis of thedispensing tube 94, and the dispensing tube 94 is disposed in such amanner that a side surface of the distal of the dispensing tube 94 thusbent or at least part of the side surface makes contact with the balloonouter surface. In this case, the discharge end exists at the distalmostend of the dispensing tube 94.

Note that the dispensing tube 94 may not necessarily be circularpipe-shaped, so long as it is capable of supplying the coating solutiontherethrough. In addition, the dispensing tube 94 may not necessarilyextend in the vertical direction, so long as it is capable ofdischarging the coating solution through the opening portion 95.

The dispensing tube 94 is preferably formed of a flexible material suchthat contact burden on the balloon 30 can be reduced and variations incontact position attendant on rotation of the balloon 30 can be absorbedby flexure of the dispensing tube 94. Examples of the applicableconstituent material of the dispending tube 94 include polyolefins suchas polyethylene or polypropylene, cyclic polyolefins, polyesters,polyamides, polyurethane, and fluoro-resins such as PTFE(polytetrafluoroethylene), ETFE (tetrafluoroethylene-ethylenecopolymer), PFA (tetrafluoroethylene-perfluoroalkyl vinyl ethercopolymer), and FEP (tetrafluoroethylene-hexafluoropropylene copolymer).However, the constituent material is not particularly limited, so longas it is flexible and deformable.

The outside diameter of the dispensing tube 94 is not particularlylimited, and may be, for example, 0.1 mm to 5.0 mm, preferably 0.15 mmto 3.0 mm, and more preferably 0.3 mm to 2.5 mm. The inside diameter ofthe dispensing tube 94 is not specifically restricted, and may be, forexample, 0.05 mm to 3.0 mm, preferably 0.1 mm to 2.0 mm, and morepreferably 0.15 mm to 1.5 mm. The length of the dispensing tube 94 isnot particularly limited, but is preferably up to 5 times the balloondiameter. The length may be, for example, 1.0 mm to 50 mm, preferably 3mm to 40 mm, and more preferably 5 mm to 35 mm.

The control unit 100 may be composed, for example, of a computer, andgenerally controls the rotation mechanism portion 60, the movementmechanism portion 80, and the application mechanism portion 90.Therefore, the control unit 100 can generally control the rotationalspeed of the balloon 30, the initial positioning of the dispensing tube94 in relation to the balloon 30, the moving speed of the dispensingtube 94 in the axial direction X relative to the balloon 30, thedischarge rate of the drug from the dispensing tube 94, etc.

The coating solution contains a water-insoluble drug and a solvent.After the coating solution is supplied onto the outer surface of theballoon 30, the solvent is volatilized, whereby the coating layer 32having a crystal layer or an amorphous layer is formed on the outersurface of the balloon 30. The balloon 30 and the coating layer 32 canbe used as a drug eluting balloon, which sustainedly releases the drugin a living body.

Water-insoluble Drug

The water-insoluble drug means a drug, which is insoluble or difficultlysoluble in water. For example, specifically, the water-insoluble drug isa drug of which the solubility in water is less than 5 mg/mL at pH 5 topH 8. The solubility may be less than 1 mg/mL, or, further, may be lessthan 0.1 mg/mL. The water-insoluble drug can include fat-soluble drugs.

Some preferred examples of the water-insoluble drug includeimmunosuppressants, for example, cyclosporines inclusive ofcyclosporine, immunoadjuvants such as rapamycin, carcinostatics such aspaclitaxel, antiviral agents or antibacterial agents, antineoplasticagents, analgesic agents and anti-inflammatory agents, antibiotics,antiepileptics, anxiolytic agents, antiparalytic agents, antagonists,neuron blocking agents, anticholinergic agents and cholinergic agents,muscarine antagonists agents and muscarine agents, antiadrenergicagents, antiarrhythmic agents, antihypertensive agents, hormonepreparations, and nutritional supplements.

The water-insoluble drug is preferably at least one selected from thegroup consisting of rapamycin, paclitaxel, docetaxel, and everolimus.The rapamycin, paclitaxel, docetaxel, and everolimus in the presentspecification include their analogs and/or derivatives so long as theanalogs and/or derivatives have equivalent drug activity to theoriginal. For example, paclitaxel and docetaxel are in an analogrelation. Rapamycin and everolimus are in a derivative relation. Amongthese, more preferable is paclitaxel.

The water-insoluble drug may further contain an excipient. The excipientis not particularly restricted so long as it is pharmaceuticallyacceptable. Examples of the excipient include water-soluble polymers,sugars, contrast agents, citric acid esters, amino acid esters, glycerolesters of short-chain monocarboxylic acids, and salts and surfactantsthat are pharmaceutically acceptable.

The excipient is preferably small in amount based on the water-insolubledrug, and preferably does not form a matrix. In addition, the excipientpreferably does not contain, but may contain, micelle, liposome,contrast agent, emulsifier, or surfactant. Further, the excipientpreferably does not contain polymer but contains only low molecularcompounds.

The solvent is not particularly limited. Tetrahydrofuran, ethanol,glycerin (also called glycerol or propane-1,2,3-triol), acetone,methanol, dichloromethane, hexane, ethyl acetate, and water can beexemplified as the solvent. Among these, preferred are mixed solvents ofsome of tetrahydrofuran, ethanol, acetone, and water.

The balloon coating method of forming the coating layer 32 containingthe water-insoluble drug on a surface of the balloon 30 by use of theaforementioned balloon coating apparatus 50 will be described below.

First, the expansion fluid is supplied through the first opening portion41 of the balloon catheter 10 into the balloon 30 to expand the balloon30; in this state, the cap 63 is put on the first opening portion 41 toachieve sealing, thereby maintaining the balloon 30 in the expandedstate. Note that the coating layer 32 can also be formed on the surfaceof the balloon 30 without expanding the balloon 30; in this case, it isunnecessary to supply the expansion fluid into the balloon 30.

Next, in a state wherein the dispensing tube 94 does not make contactwith the outer surface of the balloon 30, the balloon catheter 10 isrotatably disposed on the support base 70, and the hub 40 is connectedto the rotation mechanism portion 60.

Subsequently, the dispensing tube 94 is positioned in relation to theballoon 30 (positioning step). In the positioning step, first, theposition of the moving table 81 is regulated, to position the dispensingtube 94 in the X-axis direction. In this instance, the dispensing tube94 is positioned at the distalmost position for forming the coatinglayer 32 on the balloon 30.

Next, by operating the driving portion 84, the discharge end 97 of thedispensing tube 94 is positioned at a preset reference point B, in astate wherein the dispending tube 94 is not bent, as depicted in FIG. 3.The reference point B is the position at which the outer surface of theballoon 30 is rotated in a direction (in the present embodiment, theupward direction) opposite to the discharge direction of the dispensingtube 94, on a reference plane A (in the present embodiment, a horizontalplane) which is orthogonal to the extending direction (in the presentembodiment, the vertical direction) of the dispensing tube 94 and whichpasses through the axis X of the balloon 30. Therefore, at the positionof contact between the balloon 30 and the dispensing tube 94, theballoon 30 is rotated in the direction opposite to the dischargedirection in which the coating solution is discharged from thedispensing tube 94. Note that the extending direction of the dispensingtube 94 may not necessarily be the vertical direction, and the referenceplane A may not necessarily be a horizontal plane.

Subsequently, positioning of the discharge end 97 of the dispensing tube94 in the Y-axis direction (vertical direction) is conducted as shown inFIG. 4, by the driving portion 84. In this instance, the dispensing tube94 can be temporarily separated from the outer surface of the balloon30.

Next, positioning of the discharge end 97 of the dispensing tube 94 inthe Z-axis direction (a horizontal direction) is performed as depictedin FIG. 5, by the driving portion 84. In this instance, the dispensingtube 94 approaches the outer surface of the balloon 30 and makes contactwith the balloon 30, while being pressed against the balloon 30 andthereby bent, or without being pressed against the balloon 30 or bent.In this case, it is preferable that the length of the dispensing tube 94is up to 5 times the balloon diameter, and the dispensing tube 94 isdisposed in such a manner that its side surface on the end portion sideof its distal makes contact with the balloon surface. With thedispensing tube 94 brought into contact with the balloon 30 while beingmoved in the Z-axis direction, the dispensing tube 94 comes into contactwith the balloon 30, starting from the side of a side surface of thedispensing tube 94. Therefore, the dispensing tube 94 can bend in themanner of escaping in a direction orthogonal to the extending directionthereof, and, accordingly, there is a relatively low possibility of theballoon 30 being damaged. Alternatively, where the opening portion 95 isbrought into contact with the balloon 30 in the manner of collidingagainst the balloon 30 while the dispensing tube 94 is being moved inthe extending direction thereof, the burden on the balloon 30 isrelatively heavy, so that the balloon 30 may be deformed, or thepossibility cannot be denied that the balloon 30 may be damaged in somecases. Accordingly, it may become necessary to provide an operating stepfor checking whether or not the balloon 30 has been deformed or damaged.As mentioned above, however, the dispensing tube 94 comes into contactwith the balloon 30 starting from the side of its side surface whilebeing moved in the Z-axis direction. Therefore, it is unnecessary toprovide an operating step for checking whether or not the balloon 30 hasbeen deformed or damaged. Consequently, workability can be relativelyenhanced.

In addition, the dispensing tube 94 is subjected to positioning in theY-axis direction precedently, and is thereafter subjected to positioningin the Z-axis direction. Therefore, the dispensing tube 94 is moved inthe Y-axis direction to be temporarily separated from the balloon 30,and is thereafter moved in the Z-axis direction to make contact with theballoon 30. Accordingly, the burden on the balloon 30 is lowered ascompared, for example, to the case where positioning in the Z-axisdirection is precedently conducted to move the dispensing tube 94 in themanner of pressing the dispensing tube 94 against the balloon 30 and,thereafter, positioning in the Y-axis direction is performed to move thedispensing tube 94 while sliding the dispensing tube 94 on the outersurface of the balloon 30. Consequently, it is unnecessary to provide anoperating step for checking whether or not the balloon 30 has beendeformed or damaged. Thus, workability can be relatively enhanced.

The position at which the discharge end 97 makes contact with theballoon 30 after the dispensing tube 94 is positioned is a positionwhich is coincident with the reference plane A or a position which isdeviated from the reference plane A in a direction (in the presentembodiment, the upward side) opposite to the discharge direction of thedispensing tube 94, since the dispensing tube 94 is formed in arectilinear shape. Note that in the case where the dispensing tube 94 isnot rectilinear in shape, the dispensing tube 94 may make contact withthe position which is deviated from the reference plane A in thedischarge direction (in the present embodiment, the downward side) ofthe dispensing tube 94.

In accordance with an exemplary embodiment, a virtual position V atwhich the discharge end 97 of the dispensing tube 94 could be located ifthe dispensing tube 94 is assumed to be non-flexible is preferablydeviated from the reference plane A by an angle θ of 0 degrees to 40degrees in the rotating direction of the balloon 30. Note that thevirtual position V is the position to which the discharge end 97 wouldbe moved if the dispensing tube 94 were not bent when the discharge end97 is moved from the reference point B in the Y-axis direction and theZ-axis direction by the driving portion 84. In addition, the virtualposition V can be defined by only the distances the discharge end 97 ismoved in the Y-axis direction and the Z-axis direction by the drivingportion 84, without need to take the flexure (bending) of the dispensingtube 94 into consideration. Accordingly, the virtual position V can becontrolled relatively easily.

With the deviation of the virtual position V from the reference plane Aset to be within the range of 0 degrees to 40 degrees along the rotatingdirection of the balloon 30, the dispensing tube 94 can be restrainedfrom slipping off from the contact position, as indicated by thealternate long and two short dashes line in FIG. 5, due to a frictionalforce between the dispensing tube 94 and the balloon 30, during theapplication step which will be described later. Specifically, where thedispensing tube 94 is in contact with the balloon 30 in such a mannerthat the discharge direction is opposite to the rotating direction ofthe balloon 30, there may arise a tendency, depending on the contactconditions, that the discharge end 97 is liable to move to a stableposition at which the discharge direction of the dispensing tube 94coincides with the rotating direction of the balloon 30. With thevirtual position V located within the above-mentioned range, however,the discharge end 97 can be favorably maintained at the position atwhich the discharge direction is opposite to the rotating direction ofthe balloon 30.

Note that the discharge direction of the dispensing tube 94 can be setto be the same as the rotating direction of the balloon 30, as shown inFIG. 6A. In addition, the discharge direction of the dispensing tube 94can be set to be perpendicular to the outer circumferential surface ofthe balloon 30, as depicted in FIG. 6B.

In addition, the step of positioning the dispensing tube 94 relative tothe outer surface of the balloon 30 is not limited to theabove-mentioned procedure. For example, the dispensing tube 94 may bemoved in the Z-axis direction to make contact with the outer surface ofthe balloon 30, followed by moving the dispensing tube 94 in the Y-axisdirection. In addition, the dispensing tube 94 may be moved in theY-axis direction to thereby bring the dispensing tube 94 into contactwith the outer surface of the balloon 30.

Next, the coating solution is supplied to the dispensing tube 94 whileregulating the liquid feed rate by the liquid feed pump 93, the ballooncatheter 10 is rotated by the rotation mechanism portion 60, and themovable base 81 is moved to thereby move the dispensing tube 94gradually in the proximal direction along the X-direction. Since thedispensing tube 94 is moved relative to the balloon 30, the coatingsolution discharged from the opening portion 95 of the dispensing tube94 is applied to the outer circumferential surface of the balloon 30while drawing a spiral (application step). In this case, after thecoating solution is applied at a position where the outer surface of theballoon 30 is rotated in a direction (in the present embodiment, theupward direction) opposite to the discharge direction of the dispensingtube 94, the part coated with the coating solution does not contactother member (for example, a dispensing tube whose discharge directioncoincides with the rotating direction). Since the part coated with thecoating solution does not contact, for example, a dispensing tube whosedischarge direction coincides with the rotating direction, it ispossible to eliminate the possibility of hampering the formation of “amorphological form wherein crystals of the water-insoluble drug includea plurality of elongate bodies having each independent long axes,” andit is possible to preclude the possibility of breakage of themorphological form after the formation.

The moving speed of the dispensing tube 94 is not particularly limited,and is, for example, 0.01 mm/second to 2 mm/second, preferably 0.03mm/second to 1.5 mm/second, and more preferably 0.05 mm/second to 1.0mm/second. The discharge rate of the coating solution from thedispensing tube 94 is not specifically restricted, and is, for example,0.01 μL/second to 1.5 μL/second, preferably 0.01 μL/second to 1.0μL/second, and more preferably 0.03 μL/second to 0.8 μL/second. Therotational speed of the balloon 30 is not particularly limited, and is,for example, 10 rpm to 300 rpm, preferably 30 rpm to 250 rpm, and morepreferably 50 rpm to 200 rpm. The diameter of the balloon 30 at the timeof coating the balloon 30 with the coating solution is not specificallyrestricted, and is, for example, 1 mm to 10 mm, preferably 2 mm to 7 mm.

When the balloon catheter 10 is rotated, the balloon 30 may, in somecases, become eccentric due to bending along the axial direction X ofthe balloon 30. Since the dispensing tube 94 is flexible, however, evenif the balloon 30 becomes eccentric, the dispensing tube 94 movesfollowing up to the balloon 30, whereby good contact of these members ismaintained. Consequently, variations in the thickness of the coatingsolution applied can be restrained, and it becomes relatively easy toregulate the thickness and the morphological form of the coating layer32.

Thereafter, the solvent contained in the coating solution applied to thesurface of the balloon 30 is volatilized, and the coating layer 32containing the water-insoluble drug is formed on the surface of theballoon 30. The volatilization time is appropriately set according tothe solvent, and is, for example, approximately several seconds toseveral hundreds of seconds.

The amount of the drug contained in the coating layer 32 is notparticularly limited. The amount, in density, for example, is 0.1 μg/mm²to 10 μg/mm², preferably 0.5 μg/mm² to 5 μg/mm², more preferably 0.5μg/mm² to 4 μg/mm², and further preferably 1.0 μg/mm² to 3.5 μg/mm².

In addition, since the extending direction toward the opening portion 95of the dispensing tube 94 (discharge direction) is opposite to therotating direction of the balloon 30, the water-insoluble drug in thecoating layer 32 formed on the outer surface of the balloon 30 has itscrystals formed to include a morphological form including a plurality ofelongate bodies having each independent long axes.

The coating layer 32 wherein the crystals assume the morphological formincluding a plurality of elongate bodies having each independent longaxes can include the plurality of elongate bodies in the state offorming mutually independent elongate body shapes on the substrate (theouter surface of the balloon 30). The plurality of elongate bodies mayextend substantially outward in the circumferential direction withrespect to the balloon surface, or may be arranged in directionssubstantially parallel to the circumferential direction. The pluralityof elongate bodies may be present in the state of combination of thesearrangements, or may be present in contact with each other such that theadjacent elongate bodies form different angles. The plurality ofelongate bodies may be located with spaces (spaces not containing thecrystal) therebetween on the balloon surface. Specifically, for example,a preferable coating layer 32 is a layer wherein a plurality of elongatebodies each composed of the crystal of the water-insoluble drug andhaving a long axis are present in a brush-like pattern. The plurality ofelongate bodies are arranged in a circumferential and brush-like patternon the surface of the substrate. Each of the elongate bodies is presentindependently, and has a certain length, with one end (proximal) of thelength part being fixed to the substrate surface. The elongate body doesnot form a composite structure, and is not connected, with the adjacentelongate bodies. The long axis of the crystal is substantiallyrectilinear. The elongate body forms a predetermined angle with thesubstrate surface intersecting the long axis thereof. The predeterminedangle here is in the range of, for example, from 45 degrees to 135degrees, preferably 70 degrees to 110 degrees, and more preferably 80degrees to 100 degrees. Further preferably, the long axis of theelongate body forms an angle of, for example, substantially 90 degreeswith the substrate surface. The elongate body, at least its portion nearthe distal thereof, is hollow. A section of the elongate body in a planeorthogonal (perpendicular) to the long axis of the elongate body has avoid (hollow portion). In the elongate body thus having a void, thesection of the elongate body in a plane orthogonal (perpendicular) tothe long axis is polygonal in shape. The polygon is, for example, atetragon, a pentagon, or a hexagon. Therefore, the elongate body isformed as an elongated polyhedron that has a distal (or distal surface)and a proximal (or proximal surface), wherein a side surface portionbetween the distal (or distal surface) and the proximal (or proximalsurface) is composed of a plurality of substantially plain surfaces.This crystalline morphological form (hollow elongate body crystallinemorphological form) constitutes the whole or at least part of a plane atthe substrate surface. For example, the layer including the hollowelongate body crystalline morphological form is a layer having any ofcrystalline morphological forms represented by SEM images in FIGS. 7 to17.

The layer having the morphological form including the hollow elongatebody crystals is characterized as follows.

(1) A plurality of elongate bodies (rod-shaped bodies) havingindependent long axes, wherein the elongate bodies are hollow. Theelongate bodies are rod-like in shape.

(2) The elongate bodies having long axes, wherein many of the elongatebodies are polyhedrons of which the section in a plane orthogonal to thelong axis is a polygon. Of the elongate body crystals, not less than 50%by volume are elongated polyhedrons. Side surfaces of the polyhedronsare mainly tetrahedron. In some cases, the elongated polyhedron has aplurality of surfaces (grooves) formed at a reentrant angle with avertex extending in the long axis direction. The reentrant angle heremeans that at least one of the internal angles of the polygon of thesection of the elongate body in a plane orthogonal to the long axis isan angle greater than 180 degrees.

(3) The elongate bodies having the long axes are elongated polyhedronsbodies in many cases. When viewed in a plane orthogonal to the long axisof the elongate body, the section of the elongate body is a polygon,which is observed as a tetragon, a pentagon, or a hexagon.

(4) The plurality of elongate bodies having independent long axes arealigned with their long axes at angles in a predetermined range,preferably in the range of, for example, from 45 degrees to 135 degrees,against the substrate surface. Specifically, for example, the pluralityof elongate bodies having independent long axes stand togethersubstantially uniformly on the substrate surface. The region in whichthe elongate bodies stand together extend in the circumferentialdirection and the axial direction of the substrate surface and is formedsubstantially uniformly. The angles of the each independent elongatebodies against the substrate surface may be different each other or thesame within the predetermined range.

(5) Each of the elongate bodies having the independent long axes has itsone end (proximal) of the length part thereof fixed to the substratesurface.

(6) The morphology of a part near the substrate surface may in somecases be a stack of granular, short rod-shaped, or short curvedline-shaped crystals. Some of the elongate bodies having the long axeshave their long axes directly or indirectly on the substrate surface.Therefore, in some cases, the elongate bodies having the long axes standtogether on the stack.

(7) The length of the elongate bodies having the long axes is, forexample, preferably 5 μm to 20 μm, more preferably 9 μm to 11 μm, andfurther preferably around 10 μm. The diameter of the elongate bodieshaving the long axes is, for example, preferably 0.01 μm to 5 μm, morepreferably 0.05 μm to 4 μm, and further preferably 0.1 μm to 3 μm.

(8) On the surface of the layer including the hollow elongate bodycrystalline morphological form, there is no other morphological form(for example, an amorphous plate-shaped morphological form) mixed intherewith. In accordance with an exemplary embodiment, for example, notless than 50% by volume, more preferably not less than 70% by volume, ofthe crystals have the crystalline morphological forms of the aforesaid(1) to (7). Further preferably, substantially all the crystals have thecrystalline morphological form of the (7).

(9) In the hollow elongate body crystalline morphological form, othercompound or compounds can be present in the coating layer containing thewater-insoluble drug constituting the crystals. In that case, the othercompound or compounds are present in the state of being distributed intospaces between the plurality of crystals (elongate bodies) of thewater-insoluble drug that stand together on the substrate surface of theballoon. As for the proportions of the substances constituting thecoating layer, in this case, the proportion (by volume) of the crystalsof the water-insoluble drug is by far greater than the proportion of theother compound or compounds.

(10) In the hollow elongate body crystalline morphological form, thewater-insoluble drug constituting the crystals exists on the substratesurface of the balloon. In the coating layer on the substrate surface ofthe balloon that has the water-insoluble drug constituting the crystals,no matrix including the excipient is formed. Therefore, thewater-insoluble drug constituting the crystals is not adhered in thematrix substance. The water-insoluble drug constituting the crystals isnot embedded in a matrix substance.

(11) In the hollow elongate body crystalline morphological form, thecoating layer may contain crystal particles of the water-insoluble drugthat are regularly disposed on the substrate surface and excipientparticles of an excipient that are irregularly disposed between thecrystal particles. In this case, the molecular weight of the excipientis smaller than the molecular weight of the water-insoluble drug.Therefore, the proportion of the excipient particles per a predeterminedarea of the substrate is smaller than the proportion of the crystalparticles, and, accordingly, the excipient particles do not form amatrix. Here, the crystal particles of the water-insoluble drug may beone of the aforesaid elongate bodies, the excipient particles arepresent in the state of being by far smaller than the crystal particlesof the water-insoluble drug and dispersed between the crystal particlesof the water-insoluble drug; accordingly, in some cases, the excipientparticles may not be observed in an SEM image or a laser microscopeimage.

The crystal layer of the hollow elongate body morphological form, whendelivered into a body as a coating layer formed by coating a substratesurface of a medical device with the drug, is low in toxicity and highin stenosis-inhibition effect. The present inventors consider that thereason for this lies in that the solubility of the drug having a certaincrystal morphology after transfer to tissue and the drug's property forbeing retained in the tissue have influences on these characteristicproperties. The water-insoluble drug including the hollow elongate bodycrystal morphology, upon transfer to the tissue, is reduced in the sizeof one unit of crystal; therefore, the drug is high in the property forpermeation into the tissue. In addition, the water-insoluble drug ishigh in solubility in the tissue. The high permeation property and highsolubility permit the drug to act effectively, whereby stenosis can beinhibited. In addition, the drug is considered to be low in toxicitybecause the drug is less liable to remain as large lumps in the tissue.

In addition, the layer including the hollow elongate body crystallinemorphological form is a morphological form wherein a plurality ofsubstantially uniform elongate bodies having long axes are standingtogether substantially uniformly and regularly on the substrate surface.Therefore, the size (the length in the long axis direction) of thecrystals transferred to the tissue is as small as approximately 10 μm.For this reason, the drug can act uniformly on the lesion affected area,and its property for permeation into the tissue can be enhanced.Further, since the crystals transferred to the tissue are small in size,a situation in which an excess amount of the drug would be retained inthe lesion affected area for an excess time is obviated. For thisreason, the drug is considered to be able to show a highstenosis-inhibition effect, without exhibiting toxicity.

Where the discharge direction of the dispensing tube 94 is opposite tothe rotating direction of the balloon 30, the water-insoluble drug inthe coating layer 32 acquires a morphological form including the hollowelongate body crystalline morphological form. The principle of thisformation may be considered to lie, for example, in that the coatingsolution discharged from the opening portion 95 onto the balloon 30 isstimulated by the dispensing tube 94 attendantly on the rotation. Inaddition, in the state where a part of a side surface on the end portionside of the dispensing tube 94 (a part of the continuous length in theextending direction of the dispensing tube 94) is in contact with theouter surface of the balloon 30, the coating solution is discharged fromthe opening portion 95 onto the balloon 30. Consequently, suitablecontact can be realized between the dispensing tube 94 and the balloon30, such as to give the morphological form wherein the crystals of thewater-insoluble drug include a plurality of elongate bodies having eachindependent long axis.

In addition, the coating solution is discharged from the opening portion95 onto the balloon 30, in a region in which the balloon 30 is rotatedtoward the upper side in the vertical direction. For this reason, thedischarge direction of the dispensing tube 94, which extends downwardsuch as to ensure easy discharge of the coating solution, can berelatively easily set to be opposite to the rotating direction of theballoon 30.

If the material constituting the dispensing tube 94 coming into contactwith the balloon 30 is polyolefin (fluorine-free polyolefin) such aspolyethylene or polypropylene, the dispensing tube 94 is low in organicsolvent resistance but is high in affinity for organic solvents andsmall in contact angles, as compared to a tube made of fluororesin suchas PTFE. Accordingly, the coating solution is less liable to be repelleddue to the characteristic properties of the material of the dispensingtube 94 at the opening portion 95 and at the part of contact with theballoon 30. Therefore, unevenness is less liable to occur in coating theouter surface of the balloon 30 with the coating solution, and thedegree of uniformity of the coating layer can be regulated with highaccuracy. Specifically, by using a material having an organic solventresistance less than that of fluororesin for the dispensing tube 94, itis possible to lower the possibility of unevenness in coating the outersurface of the balloon 30 with the coating solution. In addition, wherethe material constituting the dispensing tube 94 is polyolefin such aspolyethylene or polypropylene, it is also possible to cause unevennessin coating the outer surface of the balloon 30 with the coatingsolution, by regulating at least one of the moving speed of thedispensing tube 94, the discharge rate of the coating solution, and therotational speed of the balloon 30. For this reason, by forming thedispensing tube 94 from polyolefin such as polyethylene orpolypropylene, the level of the degree of uniformity of the coatinglayer can be arbitrarily controlled.

In addition, if the material constituting the dispensing tube 94 isfluororesin such as PTFE, ETFE, PFA, and FEP, its affinity for organicsolvents is low and contact angles are large. Accordingly, the coatingsolution is strongly repelled due to the characteristic properties ofthe material of the dispensing tube 94 at the opening portion 95 and atthe part of contact with the balloon 30. Therefore, it is possible toeasily cause unevenness (non-uniformity) in coating the outer surface ofthe balloon 30 with the coating solution. Where the unevenness incoating with the coating solution is heavy, it is possible to increasethe amount of the drug actually applied to some parts, while keepingconstant the total amount of the drug contained in the coating layer 32formed on the balloon 30. By this, it is possible to cause the drug toact effectively, without increasing the burden on the living body. Theunevenness in coating is preferably a regular non-uniformity and ispreferably a stripe pattern (spiral linear body) in which linearlycoated parts are aligned in the axial direction X of the balloon 30. Byapplying the coating solution while rotating the balloon 30 relative tothe dispensing tube 94, the coating layer 32 can be easily formed whileproducing unevenness of coating in a stripe pattern. Note thatunevenness of coating is not restricted to the form of a stripe pattern;for example, a state where extremely shaded phases are formed may beadopted.

In the application step, the degree of uniformity of the coating layer32 can be controlled, for example, by using both a dispensing tube 94formed of polyolefin and another dispensing tube 94 formed offluororesin and utilizing the aforementioned different characteristicproperties. In the case of using both the dispensing tubes 94 having thedifferent characteristic properties, for example, at the time ofsequentially coating balloons 30 of a plurality of balloon catheters 10,a control of changing the dispensing tube 94 according to the balloon 30can be carried out. In addition, a control of changing the dispensingtube 94 depending on the part being coated of one balloon 30 can also beperformed.

The drug in the coating on the outer surface of the balloon 30 canassume different morphological forms such as crystalline form, amorphousform, and mixed forms thereof. In the case where the drug is of thecrystalline form, there exist various morphological forms, which differin crystal structure. Further, crystals and amorphous phases may bedisposed regularly in the coating layer 32, or may be disposedirregularly in the coating layer 32.

When the dispensing tube 94 makes contact with the outer surface of theballoon 30, a load acts on the balloon 30. With the balloon 30 rotatedin the state where the load is acting on the surface of the balloon 30,a frictional force is generated at the contact part. Then, if theextending direction (discharge direction) toward the opening portion 95of the dispensing tube 94 is opposite to the rotating direction of theballoon 30, the frictional force is amplified by the rotation of theballoon 30, whereby formation of crystals is induced.

In addition, it is considered that, with the frictional force amplified,a greater stimulus (molecular vibration) is given to the coatingsolution under the contact of the dispensing tube 94, resulting in anaccelerating effect to induce crystalline nucleation. Specifically, forexample, with the discharge direction of the dispensing tube 94 set tobe opposite to the rotating direction of the balloon 30, the frictionalforce is amplified, and, accordingly, formation of more crystallinenuclei can be expected.

In addition, where a stimulus of a constant force is given to thecoating solution in a continued manner, an effect to form crystallinenuclei of a fixed size can also be expected.

In addition, since the discharge direction of the dispensing tube 94 isopposite to the rotating direction of the balloon 30 and the frictionalforce is thereby amplified, it can be ensured that even in the case of aballoon 30 having a smooth outer surface such that a frictional force isnot easily generated thereon, a frictional force can be generatedfavorably and formation of crystals can be thereby induced. Therefore,by setting the discharge direction of the dispensing tube 94 opposite tothe rotating direction of the balloon 30, it is possible to arbitrarilygenerate a desirable frictional force in accordance with the material ofthe balloon 30 and the states of its outer surface, and thereby to formdesirable crystals.

In addition, since the balloon 30 is rotated in the direction oppositeto the discharge direction of the dispensing tube 94 while a sidesurface of the dispensing tube 94 is kept in contact with the balloon30, the coating solution discharged from the discharge end 97 spreadsthinly on the smooth balloon 30, so that a coating layer 32 having auniform thickness can be formed.

Note that the contact length in contact of the dispensing tube 94 withthe outer surface of the balloon 30 can be calculated as a theoreticalvalue which is virtually defined as the length L from an intersection N,at which the dispensing tube 94 intersects the outer surface of theballoon 30, to the discharge end 97 of the dispensing tube 94, in thecase where the dispensing tube 94 is assumed to be non-flexible, asdepicted in FIG. 39. Note that the contact length L as a theoreticalvalue is defined without taking the rotation of the balloon 30 intoconsideration; thus, the contact length L is a value when the balloon 30is stationary.

The contact length L in contact of the dispensing tube 94 with the outersurface of the balloon 30 is not particularly limited, and ispreferably, for example, 0 mm to 4.0 mm, more preferably 1.0 mm to 4.0mm. If the contact length L is too large, the frictional force is alsoincreased. In this case, the position of contact of the dispensing tube94 with the balloon 30 is not maintained, and a distal portion of thedispensing tube 94 is liable to move, in the course of operation, to aposition at which the discharge direction coincides with the rotatingdirection of the balloon 30.

In addition, the load exerted on the balloon 30 by the dispensing tube94 is preferably, for example, 0 mN to 158 mN, more preferably 1 mN to158 mN. If the load on the balloon 30 is too high, the frictional forceis also increased. In this case, the position of contact of thedispensing tube 94 with the balloon 30 is not maintained, and the distalportion of the dispensing tube 94 is liable to move, in the course ofoperation, to a position at which the discharge direction coincides withthe rotating direction of the balloon 30.

Then, the dispensing tube 94 is gradually moved in the axial direction Xwhile the balloon 30 is rotated, whereby the coating layer 32 is formedon the outer surface of the balloon 30 gradually along the axialdirection X. After the range of the part to be coated of the balloon 30is entirely formed thereon with the coating layer 32, the rotationmechanism portion 60, the movement mechanism portion 80, and theapplication mechanism portion 90 are stopped.

Thereafter, the balloon catheter 10 is detached from the balloon coatingapparatus 50, whereby coating of the balloon 30 is completed.

As has been described above, in the balloon coating method according tothe present embodiment, the coating solution is discharged while thedispensing tube 94 is kept in contact with the outer surface of theballoon 30 in such a manner that the opening portion 95 is oriented inthe direction opposite to the rotating direction of the balloon 30.Therefore, the water-insoluble drug in the coating layer 32 formed onthe outer surface of the balloon 30 can be formed in a morphologicalform wherein the crystals include a plurality of elongate bodies havingeach independent long axes. The plurality of elongate bodies may extendsubstantially outward in a circumferential direction with respect to theballoon surface, or may be arranged in a direction substantiallyparallel to the circumferential direction. The plurality of elongatebodies may be arranged in a fixed direction, or may be arranged randomlyin a plurality of directions. The plurality of elongate bodies may bepresent in the state of being combined with one another, or may bepresent in contact with one another in a state wherein the plurality ofadjacent elongate bodies form different angles with one another. Theplurality of elongate bodies are formed in such a manner that thecrystals do not include a structure wherein the crystals, instead ofassuming elongated-body shapes, are fused together during/or after theprocess of formation of the plurality of elongate bodies and, hence, donot show the elongated-body profile any more (for example, a structurewherein the crystals extend in a flat form on the balloon surface). Theballoon coating method according to the present embodiment helps enablesuch coating that a region in which drug crystals (a plurality ofelongate bodies) are absent is not formed on the balloon surface (suchcoating that the drug crystals are formed throughout the coated region).Alternatively, the balloon coating method according to the presentembodiment ensures that regions in which drug crystals (a plurality ofelongate bodies) are absent and regions in which the drug crystals arepresent can be formed, regularly or irregularly, on the balloon surface.In addition, according to the aforesaid balloon coating method, thecoating solution is discharged while the dispensing tube 94 is kept incontact with the outer surface of the balloon 30 in such a manner thatthe opening portion 95 is oriented in the direction opposite to therotating direction of the balloon 30, whereby suitable contact can begiven between the dispensing tube 94 and the balloon 30, and themorphological form and the size of the drug contained in the coatinglayer 32 can be freely set.

In addition, since the coating solution is discharged in a state where acontinuous length (a length which is continuous in the extendingdirection of the dispensing tube 94) of a side surface on the endportion side where the opening portion 95 is formed, of the dispensingtube 94, is kept in contact with the outer surface of the balloon 30,suitable contact can be realized between the dispensing tube 94 and theballoon 30 in such a manner that the crystals of the water-insolubledrug assume a morphological form which can include a plurality ofelongate bodies having each independent long axes.

In addition, in the application step, the flexible dispensing tube 94 ispressed against the outer surface of the balloon 30 while being bent,and the coating solution is discharged, which can help ensure that, evenif the balloon 30 becomes eccentric, damaging of the balloon 30 can berestrained, since the dispensing tube 94 moves following up to theballoon 30. In addition, favorable contact of the dispensing tube 94with the balloon 30 can be maintained. Accordingly, the thickness andthe morphological form of the coating layer 32 to be formed can be setwith relatively high accuracy.

In addition, in the application step, the coating solution is dischargedfrom the opening portion 95 while the dispensing tube 94 is kept incontact with a part at which the balloon 30 is rotated toward thevertically upper side, which helps enable the dispensing tube 94 to beeasily disposed in such a manner that the opening portion 95 is orientedin the direction opposite to the rotating direction of the balloon 30.

In addition, where the water-insoluble drug is rapamycin, paclitaxel,docetaxel, or everolimus, restenosis of a stenosed part in a bloodvessel can be favorably inhibited by the aforementioned water-insolubledrug the crystals of which are formed in a morphological form includinga plurality of elongate bodies having each independent long axes.

In addition, in the balloon coating method according to the presentembodiment, the dispensing tube 94 formed from polyolefin makes contactwith the balloon 30. As a result, the affinity of the dispensing tube 94for organic solvents is high and the contact angles are small, ascompared to the case of using a fluororesin-made tube, and the coatingsolution is less liable to be repelled at the opening portion 95 of thedispensing tube 94 or at the part of contact with the balloon 30.Therefore, uneven coating of the outer surface of the balloon 30 withthe coating solution is less liable to occur, and the degree ofuniformity of the coating layer 32 can be regulated with relatively highaccuracy. Further, since the degree of uniformity of the coating layer32 can be regulated with relative high accuracy, the morphological formand the size of the drug contained in the coating layer 32 can be freelyset.

In addition, where the dispensing tube 94 is formed from polyethylene orpolypropylene, affinity of the dispensing tube 94 for organic solventscan be securely enhanced and the contact angles can be assuredlyreduced, as compared to the case of a fluororesin-made tube.Consequently, the coating solution is less liable to be repelled at theopening portion 95 of the dispensing tube 94 or at the part of contactwith the balloon 30.

In addition, in the application step, the degree of uniformity of thecoating layer 32 may be controlled by using the dispensing tube 94formed of a polyolefin or another dispensing tube 94 formed of afluororesin. In this case, while the degree of uniformity of the coatinglayer 32 is enhanced by use of the dispensing tube 94 formed of thepolyolefin, unevenness of coating can be imparted to the coating layer32 by use of the other dispensing tube 94 formed of the fluororesin,and, consequently, the level of the degree of uniformity of the coatinglayer 32 can be controlled arbitrarily.

In addition, in the application step, the degree of uniformity(evenness) of the coating layer 32 may be controlled by regulating atleast one of the moving speed of the dispensing tube 94 relative to theballoon 30 in the axial direction X, the discharge rate of the coatingsolution from the dispensing tube 94, and the rotating speed of theballoon 30. In this case, the level of the degree of uniformity of thecoating layer 32 can be controlled arbitrarily.

In addition, in the balloon coating method according to the presentembodiment, the dispensing tube 94 coming into contact with the balloon30 may be formed from a fluororesin. In this case, affinity of thedispensing tube 94 for solvent is lowered and the contact angle isenlarged, so that the coating solution is strongly repelled at theopening portion 95 and at the part of contact with the balloon 30. As aresult, uneven coating of the outer surface of the balloon 30 with thecoating solution can be easily effected, and the morphological form andthe size of the drug contained in the coating layer 32 can be freelyset. In addition, where the unevenness in coating with the coatingsolution is heavy, the amount of the drug actually applied to some partscan be increased, while keeping constant the total amount of the drugcoated to the balloon 30. By this, it is possible to cause the drug toact effectively, without increasing the burden on the living body.

In addition, in the application step, the coating solution may beapplied while rotating the balloon 30 relative to the dispensing tube94, whereby a coating layer 32 showing unevenness of coating can beeasily formed while forming a stripe pattern on the outer surface of theballoon 30 from the coating solution.

In addition, in the positioning method for balloon coating in thepresent embodiment, the part where the opening portion 95 is formed, ofthe dispensing tube 94, is brought into contact with the outer surfaceof the balloon 30 by moving the dispensing tube 94 in a directionintersecting the extending direction of the dispensing tube 94.Therefore, the burden on the balloon 30 can be reduced, as compared tothe case where the dispensing tube 94 is moved in its extendingdirection to make contact with the balloon 30 in the manner of collidingagainst the balloon 30. Consequently, the dispensing tube 94 and theballoon 30 contact each other in a suitable state, so that themorphological form and the size of the water-insoluble drug contained inthe coating layer 32 can be freely set. In addition, with the burden onthe balloon 30 reduced, it is unnecessary to provide an operating stepfor checking whether or not the balloon 30 has been deformed or damaged.Consequently, workability is relatively enhanced.

In addition, the positioning method for balloon coating may furtherinclude an application step of discharging the coating solution from theopening portion 95 to apply the coating solution to the outer surface ofthe balloon 30 while moving the dispensing tube 94 relative to theballoon 30 in the axial direction of the balloon 30. In this case, thecoating solution can be applied to the balloon 30, which is inhibitedfrom being deformed or damaged in the positioning step. Therefore, thequantity, thickness and the like of the coating solution applied to theballoon 30 can be set with relatively high accuracy. Consequently, themorphological form and size of the drug contained in the coating layer32 formed can be freely set.

In addition, in the positioning step, that part of the dispensing tube94 at which the opening portion 95 for discharging the coating solutionis formed may be brought into contact with the outer surface of theballoon 30, by moving the dispensing tube 94 in a direction intersectingthe extending direction of the dispensing tube 94, after moving thedispensing tube 94 in the extending direction of the dispensing tube 94without making the dispensing tube 94 contact the balloon 30. In thiscase, the dispensing tube 94 does not contact the balloon 30 at the timeof moving the dispensing tube 94 in the extending direction thereof.Therefore, the burden on the balloon 30 is reduced, and it isunnecessary to provide an operating step for checking whether or not theballoon 30 has been deformed or damaged. Thus, workability is relativelyenhanced.

In addition, in the contact step, the dispensing tube 94 may bepositioned relative to the balloon 30 in such a manner that the virtualposition V at which the opening portion 95 would be located if thedispensing tube 94 is assumed to be non-flexible is located at aposition deviated from the reference plane A toward the rotatingdirection side of the balloon 30 by an angle, for example, within therange of 0 degrees to 40 degrees, with the axis of the balloon 30 as thevertex of the angle, in a region extending from the reference plane A ina direction opposite to the discharge direction of the dispensing tube94. In this case, the dispensing tube 94 can be inhibited from slippingoff from the contact position due to a frictional force between thedispensing tube 94 and the balloon 30, and favorable contact ismaintained. Consequently, the morphological form and size of thewater-insoluble drug contained in the coating layer 32 can be freelyset.

In addition, in the balloon coating method according to the presentembodiment, that part of the dispensing tube 94 at which the openingportion 95 is formed (a side surface of the distal of the dispensingtube 94) may be brought into contact with the outer surface of theballoon 30 by moving the dispensing tube 94 in a direction intersectingthe extending direction of the dispensing tube 94. By this, thedispensing tube 94 can be inhibited from slipping off from the contactposition due to a frictional force between the dispensing tube 94 andthe balloon 30, and favorable contact is maintained. Accordingly, themorphological form and size of the water-insoluble drug contained in thecoating layer 32 can be freely set.

Note that the present disclosure is not to be limited only to theaforementioned embodiment, and various modifications can be made by aperson skilled in the art within the technical thought of the presentdisclosure. For instance, while application of the coating solution isconducted along the direction from the distal side toward the proximalside of the balloon 30 in the aforementioned embodiment, the applicationmay be carried out along the direction from the proximal side toward thedistal side.

In addition, while the dispensing tube 94 extends downward along thevertical direction to make contact with the balloon 30 in the presentembodiment, the extending direction of the dispensing tube 94 is notspecifically restricted. For example, the extending direction may beinclined against the vertical direction, or the dispensing tube 94 mayextend toward a lateral side or an upper side.

In addition, while the outer circumferential surface of the balloon 30is circular in shape in section orthogonal to the axis in the presentembodiment, it may not be circular. The balloon coating method accordingto the present embodiment helps ensure that, even if the outercircumferential surface of the balloon is not circular in the shape, thedispensing tube 94 can move following up to the shape of the balloon, sothat the coating solution can be applied uniformly while inhibitingunevenness of coating, and the desired coating layer 32 can be suitablyformed.

In addition, while coating is applied to the balloon 30 of the ballooncatheter 10 of the over-the-wire type in the balloon coating methodaccording to the aforementioned embodiment, the coating may be appliedto a balloon of a balloon catheter of the rapid exchange type wherein aguide wire lumen is only formed in a distal portion of a catheter.

EXAMPLES

The present disclosure will now be described below by showing Examplesand Comparative Examples, but the disclosure is not limited to thefollowing Examples.

Test 1 (Verification Test Concerning Rotating Direction of Balloon)Production of Drug Eluting Balloon

Example 1

(1) Preparation of Coating Solution 1

56 mg of L-serine ethyl ester hydrochloride (CAS No. 26348-61-8) and134.4 mg of paclitaxel (CAS No. 33069-62-4) were weighed. To thesecompounds were added 1.2 mL of anhydrous ethanol, 1.6 mL oftetrahydrofuran, and 0.4 mL of RO (Reverse Osmosis film)-treated water(hereinafter referred to as RO water), to dissolve the compounds,thereby preparing a coating solution 1.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 1 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, a dispensing tube having an opening portion at adistalmost portion (the dispensing tube was formed from polyethylene)was moved toward the balloon catheter from a lateral direction(horizontal direction), and was disposed such that part of a sidesurface of the distal of the dispensing tube was set along and incontact with the outer surface of the balloon. In this instance, thedispensing tube was positioned such that the virtual position in regardof the dispensing tube is within an angular range of 0 degrees to 40degrees from the reference plane of the balloon (a horizontal planepassing through the axis of the balloon) toward the rotating directionside. Then, while keeping the side surface of the distal of thedispensing tube in contact with the outer surface of the balloon, thedrug was discharged from the distal opening portion of the dispensingtube. In this state, the balloon catheter was rotated about the axis ofthe balloon, in the direction opposite (reverse) to the drug dischargedirection. By regulating the moving speed of the dispensing tube in theaxial direction of the balloon and the rotating speed of the balloon,the drug was discharged, upon the start of rotation, at a rate of 0.053μL/second during coating. Thereafter, the thus coated balloon was dried,to produce a drug eluting balloon.

Example 2

(1) Preparation of Coating Solution 2

70 mg of L-serine ethyl ester hydrochloride and 180 mg of paclitaxelwere weighed. To these compounds were added 1.5 mL of anhydrous ethanol,2.0 mL of acetone, 0.5 mL of tetrahydrofuran, and 1 mL of RO water, todissolve the compounds, thereby preparing a coating solution 2.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 2 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, coating was conducted in the same manner as the methoddescribed in Example 1, except that the drug was discharged at a rate of0.088 μL/second. Thereafter, the thus coated balloon was dried, toproduce a drug eluting balloon.

Example 3

(1) Preparation of Coating Solution 3

70 mg of L-serine ethyl ester hydrochloride and 168 mg of paclitaxelwere weighed. To these compounds were added 1.5 mL of anhydrous ethanol,1.5 mL of tetrahydrofuran, and 1 mL of RO water, to dissolve thecompounds, thereby preparing a coating solution 3.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 3 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution 3 was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, coating was conducted in the same manner as the methoddescribed in Example 1, except that the drug was discharged at a rate of0.101 μL/second. Thereafter, the thus coated balloon was dried, toproduce a drug eluting balloon.

Example 4

(1) Preparation of Coating Solution 4

70 mg of L-serine ethyl ester hydrochloride and 180 mg of paclitaxelwere weighed. To these compounds were added 1.75 mL of anhydrousethanol, 1.5 mL of tetrahydrofuran, and 0.75 mL of RO water, to dissolvethe compounds, thereby preparing a coating solution 4.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 4 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, coating was performed in the same manner as the methoddescribed in Example 1, except that the drug was discharged at a rate of0.092 μL/second. Thereafter, the thus coated balloon was dried, toproduce a drug eluting balloon.

(1) Preparation of Coating Solution 5

37.8 mg of L-aspartate dimethyl ester hydrochloride (CAS No. 32213-95-9)and 81 mg of paclitaxel were weighed. To these compounds were added 0.75mL of anhydrous ethanol, 0.96 mL of tetrahydrofuran, and 0.27 mL of ROwater, to dissolve the compounds, thereby preparing a coating solution5.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 5 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, coating was conducted in the same manner as the methoddescribed in Example 1, except that the drug was discharged at a rate of0.055 μL/second. Thereafter, the thus coated balloon was dried, toproduce a drug eluting balloon.

Example 6

(1) Preparation of Coating Solution 6

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 6.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 6 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, coating was performed in the same manner as the methoddescribed in Example 1, except that the drug was discharged at a rate of0.101 μL/second. Thereafter, the thus coated balloon was dried, toproduce a drug eluting balloon.

Comparative Example 1

(1) Preparation of Coating Solution 7

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 6.

(2) Coating of Balloon with Drug

A balloon catheter (made by Terumo Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 3.0 mm in diameterand 20 mm in length (expandable portion) when expanded was provided. Thecoating solution 7 was applied to the balloon in an expanded state, insuch a manner that the solvent of the coating solution was volatilizedslowly and that the amount of paclitaxel in the coating would beapproximately 3 μg/mm².

Specifically, coating was conducted in the same manner as the methoddescribed in Example 1, except that the drug was discharged at a rate of0.101 μL/second and the balloon catheter was rotated about the long axisin the direction coincident with the drug discharge direction.Thereafter, the thus coated balloon was dried, to produce a drug elutingballoon.

Scanning Electron Microscope Observation (SEM) of Coating Layer of DrugEluting Balloon

With respect to the drug eluting balloons of Examples 1 to 6 (FIGS. 7 to17) and Comparative Example 1 (FIG. 18), the drug eluting balloon afterdrying was cut to an appropriate size, the cut piece was placed on asupport base, and platinum was vapor deposited thereon from above. Withrespect to the samples obtained upon platinum vapor deposition, thesurface and the inside of the coating layer were observed under ascanning electron microscope (SEM).

Results of Test 1

For the coating layers of Examples 1 to 6 wherein the dischargedirection was opposite to the rotating direction, it was seen from theSEM pictures that a crystal layer of a morphological form of hollowelongate bodies projecting (in inverted state) outward in thecircumferential direction with reference to the balloon surface wasobserved.

In Examples 1 to 6, as shown in FIGS. 7 to 17, it was observed that acoating layer including a morphological form of hollow elongate bodieswas formed, and uniform paclitaxel crystals in the form of hollowelongate bodies approximately 10 μm in length were evenly formed on theouter surface of the balloon. The paclitaxel crystals in the form ofhollow elongate bodies had long axes, and the elongate bodies(approximately 10 μm) having the long axes were formed to besubstantially perpendicular to the outer surface of the balloon. Thediameter of the elongate bodies was approximately 2 μm. In addition, thesections of the elongate bodies in a plane orthogonal to the long axiswere polygonal in shape. The polygons here had, for example, tetragons.Further, these substantially uniform hollow elongate body-shapedcrystals of paclitaxel were formed in the same morphological form(structure and shape), evenly and densely (in substantially the samedensity) throughout the outer surface of the balloon.

Specifically, for example, in Comparative Example 1 wherein thedischarge direction was coincident with the rotating direction,amorphous phases and crystals were mixedly present in the same plane, asseen in the SEM picture shown in FIG. 18.

Test 2 (Verification Test Concerning Constituent Material of Balloon)Production of Drug Eluting Balloon

Example 7

(1) Preparation of Coating Solution 8

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 8.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 7.0 mm in diameterand 200 mm in length (expandable portion) when expanded was provided.The coating solution 8 was applied to the balloon in an expanded state,in such a manner that the solvent of the coating solution wasvolatilized slowly and that the amount of paclitaxel in the coatingwould be approximately 3 μg/mm².

Specifically, a dispensing tube (outside diameter, 0.61 mm; insidediameter, 0.28 mm; the dispensing tube was formed from polyethylene)having an opening portion at a distalmost portion was moved toward theballoon catheter from a lateral direction (horizontal direction), andwas disposed such that part of a side surface of the distal of thedispensing tube was set along and in contact with the outer surface ofthe balloon. While keeping the side surface of the distal of thedispensing tube in contact with the outer surface of the balloon, thedrug was discharged from the distal opening portion of the dispensingtube. In this state, the balloon catheter was rotated about the axis ofthe balloon in the direction opposite (reverse) to the drug dischargedirection. By regulating the moving speed of the dispensing tube in theaxial direction of the balloon and the rotating speed of the balloon,the drug was discharged, upon the start of rotation, at a rate of 0.378μL/second during coating. Thereafter, the thus coated balloon was dried,to produce a drug eluting balloon.

Example 8

(1) Preparation of Coating Solution 9

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 9.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 4.0 mm in diameterand 200 mm in length (expandable portion) when expanded was provided.The coating solution 9 was applied to the balloon in an expanded state,in such a manner that the solvent of the coating solution wasvolatilized slowly and that the amount of paclitaxel in the coatingwould be approximately 3 μg/mm².

Specifically, coating was conducted in the same manner as the methoddescribed in Example 7, except that the drug was discharged by adispensing tube (outside diameter, 0.99 mm; inside diameter, 0.61 mm;the dispensing tube was formed from polypropylene) at a rate of 0.191μL/second. Thereafter, the thus coated balloon was dried, to produce adrug eluting balloon.

Example 9

A drug eluting balloon was produced under the same conditions as inExample 8, except that the drug discharge rate was 0.240 μL/second.

Comparative Example 2

(1) Preparation of Coating Solution 10

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 10.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from PTFE) measuring 7.0 mm in diameter and 200 mmin length (expandable portion) when expanded was provided. The coatingsolution 10 was applied to the balloon in an expanded state, in such amanner that the solvent of the coating solution was volatilized slowlyand that the amount of paclitaxel in the coating would be approximately3 μg/mm².

Specifically, coating was performed in the same manner as the methoddescribed in Example 7, except that the drug was discharged by adispensing tube (outside diameter, 0.60 mm; inside diameter, 0.30 mm;the dispensing tube was formed from PTFE) at a rate of 0.335 μL/second.Thereafter, the thus coated balloon was dried, to produce a drug elutingballoon.

Comparative Example 3

(1) Preparation of Coating Solution 11

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 11.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 4.0 mm in diameterand 200 mm in length (expandable portion) when expanded was provided.The coating solution 11 was applied to the balloon in an expanded state,in such a manner that the solvent of the coating solution wasvolatilized slowly and that the amount of paclitaxel in the coatingwould be approximately 3 μg/mm².

Specifically, coating was conducted in the same manner as the methoddescribed in Example 7, except that the drug was discharged by adispensing tube (outside diameter, 0.304 mm; inside diameter, 0.152 mm;the dispensing tube was formed from PTFE) at a rate of 0.145 μL/secondand the balloon catheter was rotated about the axis of the balloon inthe direction coincident with the drug discharge direction. Thereafter,the thus coated balloon was dried, to produce a drug eluting balloon.

Comparative Example 4

(1) Preparation of Coating Solution 12

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 12.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 7.0 mm in diameterand 200 mm in length (expandable portion) when expanded was provided.The coating solution 12 was applied to the balloon in an expanded state,in such a manner that the solvent of the coating solution wasvolatilized slowly and that the amount of paclitaxel in the coatingwould be approximately 3 μg/mm².

Specifically, coating was performed in the same manner as the methoddescribed in Example 7, except that the drug was discharged by adispensing tube (outside diameter, 0.90 mm; inside diameter, 0.51 mm;the dispensing tube was formed from All-Teflon (registered trademark))at a rate of 0.378 μL/second. Thereafter, the thus coated balloon wasdried, to produce a drug eluting balloon.

Laser Microscope Observation of Drug Coating Layer of Drug ElutingBalloon

In regard of the drug eluting balloons of Examples 7 to 9 (FIGS. 19 to24) and Comparative Examples 2 to 4 (FIGS. 25 to 30), the surface wasphotographed, and the surface of the coating layer was observed under alaser microscope.

Results of Test 2

In Example 7 wherein dispensing tube formed of a(non-fluorine-containing) polyolefin (polyethylene or polypropylene) wasused as constituent material, it was observed that the coating layercovers the balloon uniformly without any unevenness, and the balloon wasnon-exposed over substantially the whole surface area.

In Examples 7 and 8, as seen in the pictures shown in FIGS. 19 and 21,the coating layer was observed to be coating the outer surface of theballoon uniformly without any unevenness over the area ranging from adistal portion to a proximal portion. In addition, from FIG. 20 showinga laser microscope image of a central portion P1 of the balloon ofExample 7 and FIG. 22 showing a laser microscope image of a centralportion P2 of the balloon of Example 8, it was observed that thewater-insoluble drug in the coating layer on the balloon is formed in amorphological form including hollow elongate body crystals.

In addition, in Example 9 wherein the constituent material of thedispensing tube is a polyolefin (polypropylene), it was observed, fromthe picture shown in FIG. 23 and from FIG. 24 showing a laser microscopeimage of a central portion P3 of the balloon, that a non-uniform coatinglayer such that the outer surface of the balloon is partly exposed wasformed, by only changing the discharge rate as compared to Example 8. Asa result, it was confirmed that when the constituent material of thedispensing tube is a polyolefin (polypropylene), the coating layer onthe outer surface of the balloon could not only be formed in a uniformstate but also be formed in a non-uniform state.

Specifically, for example, in Comparative Examples 2 to 4 wherein theconstituent material is a fluororesin, as shown in FIGS. 25 to 30, thecoating layer was non-uniformly coated with much unevenness of coating,and parts where the balloon was exposed were observed, in the arearanging from a distal portion to a proximal portion of the outer surfaceof the balloon. The unevenness of coating was formed in a stripe patternsuch that the coating layers are aligned along the axial direction ofthe balloon. From FIG. 26 showing a laser microscope image of a centralportion P4 of the balloon of Comparative Example 2, FIG. 28 showing alaser microscope image of a central portion P5 of the balloon ofComparative Example 3, and FIG. 30 showing a laser microscope image of acentral portion P6 of the balloon of Comparative Example 4, it wasobserved that the crystals of the water-insoluble drug in the coatinglayer were mostly formed in the manner of lying along the surface of theballoon.

Test 3 (Verification Test Concerning Contact Position Between DispensingTube and Balloon)

Production of Drug Eluting Balloon

Example 10

(1) Preparation of Coating Solution 13

140 mg of L-serine ethyl ester hydrochloride and 336 mg of paclitaxelwere weighed. To these compounds were added 3.0 mL of anhydrous ethanol,4.0 mL of acetone, 1.0 mL of tetrahydrofuran, and 2 mL of RO water, todissolve the compounds, thereby preparing a coating solution 13.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 7.0 mm in diameterand 200 mm in length (expandable portion) when expanded was provided.The coating solution 13 was applied to the balloon in an expanded state,in such a manner that the solvent of the coating solution wasvolatilized slowly and that the amount of paclitaxel in the coatingwould be approximately 3 μg/mm².

Specifically, a dispensing tube (outside diameter, 0.61 mm; insidediameter, 0.28 mm; length, 6 mm; the dispensing tube was formed frompolyethylene) having an opening portion at a distalmost portion was putin contact with a reference position (deviated from the reference planetoward the balloon rotating direction side by an angle of 0 degrees) ofthe outer surface of the balloon in a non-bending manner, and thisposition was made to be the drug-discharging position without moving thedispensing tube in the vertical direction (Y-axis direction) or ahorizontal direction (Z-axis direction). The virtual position of thedistal portion of the dispensing tube in this case was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 0 degrees, with the axis of the balloon asthe vertex of the angle. Thereafter, while keeping a side surface of thedistal of the dispensing tube in contact with the outer surface of theballoon, the drug was discharged from the distal opening portion of thedispensing tube. In this state, the balloon catheter was rotated aboutthe axis of the balloon in the direction opposite (reverse) to the drugdischarge direction. By regulating the moving speed of the dispensingtube in the axial direction of the balloon and the rotating speed of theballoon, the drug was discharged, upon the start of rotation, at a rateof 0.378 μL/second during coating. Thereafter, the thus coated balloonwas dried, to produce a drug eluting balloon.

Example 11

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 0.6 mm upward in the verticaldirection (Y-axis direction), and was then moved by 2.0 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 21.8 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L (theoretical value; see FIG. 39) incontact of the dispensing tube with the balloon outer surface was 3.2mm.

Example 12

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.5 mm upward in the verticaldirection (Y-axis direction), and was then moved by 0.9 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 30.0 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe outer surface of the balloon was 1.0 mm, and the load exerted on theballoon outer surface due to the contact of the dispensing tube was 1mN. The load was measured by attaching the dispensing tube to apush-pull gauge, and measuring a reaction force acting on the dispensingtube. Note that the same load measuring method as this was used also inother Examples and Comparative Examples.

Example 13

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 0.4 mm upward in the verticaldirection (Y-axis direction), and was then moved by 2.7 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 26.6 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 4.0 mm, and the load exerted on theballoon outer surface due to the contact of the dispensing tube was 7mN.

Example 14

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.0 mm upward in the verticaldirection (Y-axis direction), and was then moved by 2.0 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 33.7 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 2.8 mm.

Example 15

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.7 mm upward in the verticaldirection (Y-axis direction), and was then moved by 1.4 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 39.0 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 1.5 mm, and the load exerted on theballoon outer surface due to the contact of the dispensing tube was 3mN.

Example 16

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 0.2 mm upward in the verticaldirection (Y-axis direction), and was then moved by 0.6 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 3.9 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 1.9 mm, and the load exerted on theballoon outer surface due to the contact of the dispensing tube was 7mN.

Example 17

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 0.2 mm upward in the verticaldirection (Y-axis direction), and was then moved by 1.3 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 5.2 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 2.8 mm, and the load exerted on theballoon outer surface due to the contact was 15 mN.

Example 18

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.2 mm upward in the verticaldirection (Y-axis direction), and was then moved by 0.8 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 24.0 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 1.2 mm.

Example 19

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.1 mm upward in the verticaldirection (Y-axis direction), and was then moved by 1.5 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 28.8 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 2.2 mm.

Example 20

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.1 mm upward in the verticaldirection (Y-axis direction), and was then moved by 1.6 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 30.1 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 2.3 mm, and the load exerted on theballoon outer surface due to the contact of the dispensing tube was 24mN.

Example 21

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with thereference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.2 mm upward in the verticaldirection (Y-axis direction), and was then moved by 1.9 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 36.9 degrees, with the axis of the balloonas the vertex of the angle.

In addition, the contact length L in contact of the dispensing tube withthe balloon outer surface was 2.6 mm.

Example 22

(1) Preparation of Coating Solution 14

560 mg of L-serine ethyl ester hydrochloride and 1,344 mg of paclitaxelwere weighed. To these compounds were added 11.0 mL of anhydrousethanol, 16.0 mL of acetone, 4.0 mL of tetrahydrofuran, and 9.0 mL of ROwater, to dissolve the compounds, thereby preparing a coating solution14.

(2) Coating of Balloon with Drug

A balloon catheter (made by Kaneka Corporation; the balloon (expandableportion) was formed from nylon elastomer) measuring 7.0 mm in diameterand 200 mm in length (expandable portion) when expanded was provided.The coating solution 14 was applied to the balloon in an expanded state,in such a manner that the solvent of the coating solution wasvolatilized slowly and that the amount of paclitaxel in the coatingwould be approximately 3 μg/mm².

Specifically, a dispensing tube (outside diameter, 1.50 mm; insidediameter, 1.00 mm; length, 10 mm; the dispensing tube was formed frompolyethylene) having an opening portion at a distalmost portion was putin contact with the virtual position of the outer surface of theballoon, and the production was conducted. In bringing the dispensingtube into contact with the balloon, the distal of the dispensing tubewas put in contact with the reference position of the outer surface ofthe balloon in a non-bending manner, and was moved from this position by0.5 mm in a horizontal direction (Z-axis direction), whereby part of aside surface of the distal of the dispensing tube was set along and incontact with the outer surface of the balloon. The virtual position ofthe distal portion of the dispensing tube in this instance was locatedat a position deviated from the reference plane toward the balloonrotating direction by an angle of 0 degrees, with the axis of theballoon as the vertex of the angle. In addition, the length over whichthe dispensing tube made contact with the balloon outer surface was 1.9mm, and the load exerted on the balloon outer surface due to the contactof the dispensing tube was 42 mN. Thereafter, while keeping a sidesurface of the distal of the dispensing tube in contact with the outersurface of the balloon, the drug was discharged from the distal openingportion of the dispensing tube. In this state, the balloon catheter wasrotated about the axis of the balloon in the direction opposite(reverse) to the drug discharge direction. By regulating the movingspeed of the dispensing tube in the axial direction of the balloon andthe rotating speed of the balloon, the drug was discharged, upon thestart of rotation, at a rate of 0.7122 μL/second during coating.Thereafter, the thus coated balloon was dried, to produce a drug elutingballoon.

Example 23

A drug eluting balloon was produced under the same conditions as inExample 22, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, and was moved from this position by 0.9 mm in a horizontaldirection (Z-axis direction), whereby part of a side surface of thedistal of the dispensing tube was set along and in contact with theouter surface of the balloon. The virtual position of the distal portionof the dispensing tube in this instance was located at a positiondeviated from the reference plane toward the balloon rotating directionside by an angle of 0 degrees, with the axis of the balloon as thevertex of the angle. In addition, the contact length L in contact of thedispensing tube with the balloon outer surface was 2.5 mm, and the loadexerted on the balloon outer surface due to the contact of thedispensing tube was 72 mN.

Example 24

A drug eluting balloon was produced under the same conditions as inExample 22, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, and was moved from this position by 1.5 mm in a horizontaldirection (Z-axis direction), whereby part of a side surface of thedistal of the dispensing tube was set along and in contact with theouter surface of the balloon. The virtual position of the distal portionof the dispensing tube in this instance was located at a positiondeviated from the reference plane toward the balloon rotating directionside by an angle of 0 degrees, with the axis of the balloon as thevertex of the angle. In addition, the contact length L in contact of thedispensing tube with the balloon outer surface was 3.2 mm, and the loadexerted on the balloon outer surface due to the contact of thedispensing tube was 117 mN.

Example 25

A drug eluting balloon was produced under the same conditions as inExample 22, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, and was moved from this position by 2.4 mm in a horizontaldirection (Z-axis direction), whereby part of a side surface of thedistal of the dispensing tube was set along and in contact with theouter surface of the balloon. The virtual position of the distal portionof the dispensing tube in this instance was located at a positiondeviated from the reference plane toward the balloon rotating directionside by an angle of 0 degrees, with the axis of the balloon as thevertex of the angle. In addition, the contact length L in contact of thedispensing tube with the balloon outer surface was 4.1 mm, and the loadexerted on the balloon outer surface due to the contact of thedispensing tube was 158 mN.

Comparative Example 5

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.7 mm upward in the verticaldirection (Y-axis direction), and was then moved by 2.1 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 50.5 degrees, with the axis of the balloonas the vertex of the angle.

Comparative Example 6

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.4 mm upward in the verticaldirection (Y-axis direction), and was then moved by 2.4 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 51.8 degrees, with the axis of the balloonas the vertex of the angle.

Comparative Example 7

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.8 mm upward in the verticaldirection (Y-axis direction), and was then moved by 1.7 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 45.0 degrees, with the axis of the balloonas the vertex of the angle.

Comparative Example 8

A drug eluting balloon was produced under the same conditions as inExample 10, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, was moved from this position by 1.1 mm upward in the verticaldirection (Y-axis direction), and was then moved by 2.4 mm in ahorizontal direction (Z-axis direction), whereby part of a side surfaceof the distal of the dispensing tube was set along and in contact withthe outer surface of the balloon. The virtual position of the distalportion of the dispensing tube in this instance was located at aposition deviated from the reference plane toward the balloon rotatingdirection side by an angle of 45.0 degrees, with the axis of the balloonas the vertex of the angle.

Comparative Example 9

A drug eluting balloon was produced under the same conditions as inExample 22, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, and was moved from this position by 3.0 mm in a horizontaldirection (Z-axis direction), whereby part of a side surface of thedistal of the dispensing tube was set along and in contact with theouter surface of the balloon. The virtual position of the distal portionof the dispensing tube in this instance was located at a positiondeviated from the reference plane toward the balloon rotating directionside by an angle of 0 degrees, with the axis of the balloon as thevertex of the angle. In addition, the contact length L in contact of thedispensing tube with the balloon outer surface was 4.6 mm, and the loadexerted on the balloon outer surface due to the contact of thedispensing tube was 182 mN.

Comparative Example 10

A drug eluting balloon was produced under the same conditions as inExample 22, except for the position of contact of the dispensing tubewith the balloon. In bringing the dispensing tube into contact with theballoon, the distal of the dispensing tube was put in contact with areference position of the outer surface of the balloon in a non-bendingmanner, and was moved from this position by 3.4 mm in a horizontaldirection (Z-axis direction), whereby part of a side surface of thedistal of the dispensing tube was set along and in contact with theouter surface of the balloon. The virtual position of the distal portionof the dispensing tube in this instance was located at a positiondeviated from the reference plane toward the balloon rotating directionside by an angle of 0 degrees, with the axis of the balloon as thevertex of the angle. In addition, the contact length L in contact of thedispensing tube with the balloon outer surface was 4.9 mm, and the loadexerted on the balloon outer surface due to the contact of thedispensing tube was 190 mN.

Observation of Slip-off of Dispensing Tube

In Examples 10 to 21 and Comparative Examples 5 to 8, it was observedwhether or not the dispensing tube slips off from the balloon in such amanner that the discharge direction becomes coincident with the rotatingdirection of the balloon, from the state where the dispensing tube is incontact with the balloon in such a manner that the discharge directionis opposite to the rotating direction of the balloon, at the time ofcoating with the drug. In addition, with regard to the drug elutingballoons of Comparative Examples 10 to 15 and Comparative Example 5, theballoon surface was photographed.

In addition, in Examples 22 to 25 and Comparative Examples 9 and 10, itwas observed whether or not the dispensing tube slips off from theballoon in such a manner that the discharge direction becomes coincidentwith the balloon rotating direction, from the state where the dispensingtube is in contact with the balloon in such a manner that the dischargedirection is opposite to the balloon rotating direction, at the time ofcoating with the drug. In addition, with regard to the drug elutingballoons of Examples 22 to 25, the surface was photographed.

Results of Test 3

Table 1 and FIG. 31 show the results of the observation of whether ornot the dispensing tube slips off from the balloon, whereas FIGS. 32 to38 show the pictures of the surfaces of the drug eluting balloons ofExamples 10 to 15 and Comparative Example 5.

In addition, Table 2 and FIG. 40 show the results of the observation ofwhether or not the dispensing tube slips off from the balloon inExamples 22 to 25 and Comparative Examples 9 and 10, and FIGS. 41 to 48show the pictures of the surfaces of the drug eluting balloons ofExamples 22 to 25.

TABLE 1 Moving Moving Angle Load distance distance of exerted ContactSlip-off in Y-axis in Z-axis virtual on length of direction directionposition balloon of tube dispensing (mm) (mm) (°) (mN) (mm) tube Example10 0.0 0.0 0.0 — 0.0 absent Example 11 0.6 2.0 21.8 — 3.2 absent Example12 1.5 0.9 30.0 1 1.0 absent Example 13 0.4 2.7 26.6 7 4.0 absentExample 14 1.0 2.0 33.7 — 2.8 absent Example 15 1.7 1.4 39.0 3 1.5absent Example 16 0.2 0.6 3.9 7 1.9 absent Example 17 0.2 1.3 5.2 15 2.8absent Example 18 1.2 0.8 24.0 — 1.2 absent Example 19 1.1 1.5 28.8 —2.2 absent Example 20 1.1 1.6 30.1 24 2.3 absent Example 21 1.2 1.9 36.9— 2.6 absent Comparative 1.7 2.1 50.5 — — present Example 5 Comparative1.4 2.4 51.8 — — present Example 6 Comparative 1.8 1.7 45.0 — — presentExample 7 Comparative 1.1 2.4 45.0 — — present Example 8

TABLE 2 Moving Moving distance distance Angle Load Contact in in ofexerted length Slip-off Y-axis Z-axis virtual on of of directiondirection position balloon tube dispensing (mm) (mm) (°) (mN) (mm) tubeExample 22 0 0.5 0 42 1.9 absent Example 23 0 0.9 0 72 2.5 absentExample 24 0 1.5 0 117 3.2 absent Example 25 0 2.4 0 158 4.1 absentComparative 0 3 0 182 4.6 present Example 9 Comparative 0 3.4 0 190 4.9present Example 10

In Examples 10 to 21 wherein the virtual position of the distal portionof the dispensing tube was located at a position deviated from thereference plane toward the balloon rotating direction side by an angleof 0 degrees to 40 degrees, with the axis of the balloon as the vertexof the angle, it was observed that the position of contact of thedispensing tube with the balloon was maintained favorably, as shown inTable 1 and FIG. 31. In addition, from the pictures of Examples 10 to 15shown in FIGS. 32 to 37, it was observed that a uniform coating layerfree of unevenness of coating was formed over the whole area of theouter surface of the balloon.

Specifically, for example, in Comparative Examples 5 to 8 wherein thevirtual position of the distal portion of the dispensing tube waslocated at a position deviated from the reference plane toward theballoon rotating direction side by an angle of more than 40 degrees,with the axis of the balloon as the vertex of the angle, it was seenfrom Table 1 and FIG. 31 that the position of contact of the dispensingtube with the balloon was not maintained, that is, the distal portion ofthe dispensing tube moved, in the course of coating, to such a positionthat the discharge direction becomes coincident with the rotatingdirection of the balloon. In Comparative Example 5, the movement of thedispensing tube occurred at the position of P7 shown in FIG. 38, and, atthis position, unevenness (non-uniformity) was observed in the coatinglayer completed.

In Examples 10 to 21 wherein a polyethylene-made dispensing tube havingan outside diameter of 0.61 mm and an inside diameter of 0.28 mm wasused, it was observed, as shown in Table 1, that the position of contactof the dispensing tube with the balloon is maintained favorably in thecase where the contact length of the tube is not more than 4.0 mm.According to Examples 10 to 21, therefore, the contact length of thetube is preferably 0 mm to 4.0 mm, more preferably 1.0 mm to 4.0 mm.

In addition, in Examples 10 to 21, it was observed that the position ofcontact of the dispensing tube with the balloon is maintained favorablyin the case where the load exerted on the balloon is not more than 24mN. According to Examples 10 to 21, therefore, the load exerted on theballoon is preferably 0 mN to 24 mN, more preferably 1 mN to 24 mN.

As shown in Table 2 and FIG. 38, in Examples 22 to 25 and ComparativeExamples 9 and 10 wherein a polyethylene-made dispensing tube having anoutside diameter of 1.50 mm and an inside diameter of 1.00 mm was used,it was observed that the position of contact of the dispensing tube withthe balloon is maintained favorably in Examples 22 to 25 wherein thecontact length was not more than 4.1 mm. Specifically, for example, inComparative Examples 9 and 10 wherein the contact length was not lessthan 4.6 mm, it was observed that the position of contact of thedispensing tube with the balloon is not maintained, and the distalportion of the dispensing tube moved, in the course of coating, to sucha position that the discharge direction becomes coincident with therotating direction of the balloon. According to Examples 22 to 25,therefore, the contact length of the tube is preferably 0 mm to 4.1 mm,more preferably 1.9 mm to 4.1 mm.

In addition, as shown in Table 1, in Examples 22 to 25, it was observedthat the position of contact of the dispensing tube with the balloon ismaintained favorably in the case where the load exerted on the balloonis not more than 158 mN. According to Examples 22 to 25, therefore, theload exerted on the balloon is preferably 0 mN to 158 mN, morepreferably 42 mN to 158 mN.

In addition, from the pictures of Examples 22 to 25 shown in FIGS. 41,43, 45, and 47, it was observed that a uniform coating layer free ofunevenness of coating was formed over the whole area of the outersurface of the balloon. In the coating layers of Examples 22 to 25, acrystal layer of a morphological form including hollow elongate bodiesprojecting outward in the circumferential direction with respect to theballoon surface was observed, as seen from the SEM pictures shown inFIGS. 42, 44, 46, and 48.

The detailed description above describes a balloon coating method. Theinvention is not limited, however, to the precise embodiments andvariations described. Various changes, modifications and equivalents caneffected by one skilled in the art without departing from the spirit andscope of the invention as defined in the accompanying claims. It isexpressly intended that all such changes, modifications and equivalentswhich fall within the scope of the claims are embraced by the claims.

What is claimed is:
 1. A balloon coating method for forming a coatinglayer containing a drug on an outer surface of a balloon of a ballooncatheter, the balloon coating method comprising: an application step inwhich, where a dispensing tube for supplying a coating solutioncontaining the drug and a solvent is formed at an end portion of thedispensing tube, the dispensing tube having an outer diameter and aninner diameter, and an opening portion for discharging the coatingsolution from the inner diameter and through the opening portion andwhen a continuous length of a side surface of an opening portion-formedend portion side of the dispensing tube is kept in contact with theouter surface of the balloon in such a manner as to be oriented to arotating direction of the balloon while the balloon is rotated about anaxis of the balloon, the coating solution is discharged through theopening portion and applied to the outer surface of the balloon whilethe dispensing tube is moved relative to the balloon in an axialdirection of the balloon.
 2. The balloon coating method according toclaim 1, wherein in the application step, the coating solution isdischarged, with the dispensing tube being pressed against the outersurface of the balloon.
 3. The balloon coating method according to claim1, wherein in the application step, the coating solution is discharged,with the dispensing tube being pressed against the outer surface of theballoon while being bent.
 4. The balloon coating method according toclaim 1, wherein in the application step, the coating solution isdischarged through the opening portion while the dispensing tube is keptin contact with that portion of the balloon which is rotating toward anupper side in a vertical direction.
 5. The balloon coating methodaccording to claim 1, wherein the drug is a water-insoluble drug, thewater insoluble drug being rapamycin, paclitaxel, docetaxel, oreverolimus.
 6. A balloon of a balloon catheter, the balloon coatedaccording to the balloon coating method of claim
 1. 7. The methodaccording to claim 1, wherein the dispensing tube has a length of up tofive times a diameter of the balloon.
 8. The method according to claim1, comprising: in the application step, controlling a degree ofuniformity of the coating layer by regulating at least one of a movingspeed of the dispensing tube relative to the balloon in an axialdirection, a discharge rate of the coating solution from the dispensingtube, and a rotating speed of the balloon; and wherein the balloon ofthe balloon catheter is positioned horizontally, and the dispensing tubeis a vertically extending dispensing tube.
 9. The method according toclaim 1, wherein the dispensing tube is formed from a polyethylene, apolypropylene, a polyolefin, or a fluororesin.
 10. The method accordingto claim 1, further comprising: a positioning step in which thedispensing tube is moved, from a state of non-contact with the balloon,in a direction intersecting an extending direction of the dispensingtube, and the continuous length of the side surface of the openingportion-formed end portion side of the dispensing tube is placed incontact with the outer surface of the balloon.
 11. A method for forminga coating layer containing a drug on an outer surface of a balloon of aballoon catheter, the method comprising: supplying a coating solutioncontaining the drug and a solvent through a distal portion of adispensing tube, the dispensing tube having an outer diameter and aninner diameter, and an opening portion for discharging the coatingsolution from the inner diameter and through the distal portion of thedispensing tube; keeping in contact a continuous length of a sidesurface of the distal portion of the dispensing tube with the outersurface of the balloon in such a manner as to be oriented to a rotatingdirection of the balloon, wherein the continuous length of the sidesurface along an extending direction of the dispensing tube in contactwith the outer surface of the balloon is 1 mm to 4 mm; rotating theballoon about an axis of the balloon; and discharging the coatingsolution through the opening portion and applied to the outer surface ofthe balloon while the dispensing tube is moved relative to the balloonin an axial direction of the balloon.
 12. The method according to claim11, comprising: discharging the coating solution with the dispensingtube being pressed against the outer surface of the balloon.
 13. Themethod according to claim 11, comprising: discharging the coatingsolution through the opening portion while the dispensing tube is keptin contact with that portion of the balloon which is rotating toward anupper side in a vertical direction.
 14. The method according to claim11, wherein the drug is a water-insoluble drug, the water-insoluble drugbeing rapamycin, paclitaxel, docetaxel, or everolimus.
 15. A balloon ofa balloon catheter, the balloon coated according to the method of claim11.
 16. The method according to claim 11, wherein the dispensing tubehas a length of up to five times a diameter of the balloon.
 17. Themethod according to claim 11, comprising: controlling a degree ofuniformity of the coating layer by regulating at least one of a movingspeed of the dispensing tube relative to the balloon in an axialdirection, a discharge rate of the coating solution from the dispensingtube, and a rotating speed of the balloon; and wherein the balloon ofthe balloon catheter is positioned horizontally, and the dispensing tubeis a vertically extending dispensing tube.
 18. The method according toclaim 11, wherein the dispensing tube is formed from a polyethylene, apolypropylene, a polyolefin, or a fluororesin.
 19. The method accordingto claim 11, further comprising: moving the dispensing tube from a stateof non-contact with the balloon, in a direction intersecting theextending direction of the dispensing tube; and placing the continuouslength of the side surface of the opening portion-formed end portionside of the dispensing tube in contact with the outer surface of theballoon.